GPR25 antagonization for treatment of autoimmune diseases

Abstract

Provided herein are methods of treating one or more of asthma, an autoimmune disease, or a fibrotic disease in a subject comprising, consisting of, or consisting essentially of administering to the subject an effective amount of an agent to inhibit the activity of a population of T-cells expressing GPR25, thereby treating the one or more of asthma, the autoimmune disease, or fibrotic disease in the subject.

Description

[0001]Atty Docket No.116639-2730 GPR25 ANTAGONIZATION FOR TREATMENT OF AUTOIMMUNE DISEASES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No.63 / 611,064, filed December 15, 2023, the contents of which is incorporated herein by reference in their entireties. FIELD OF THE DISCLOSURE The present disclosure generally relates to the treatment of asthma, autoimmune diseases, or fibrotic diseases by antagonizing G Protein-Coupled Receptor 25 (GPR25). BACKGROUND OF THE DISCLOSURE The following description of the background of the present technology is provided simply as an aid in understanding the present technology and is not admitted to describe or being prior art to the present technology. G Protein-Coupled Receptor 25 (GPR25) is expressed in Tissue-resident memory CD8+T (TRM) cells, which are a distinct population of memory T cells that primarily resides within tissues and respond immediately against pathogens invading barrier tissues, thus representing the first-line of defense. GPRs are the largest superfamily of transmembrane receptors in the genome, they interact with a large number of extracellular ligands and transmit intracellular signals by activating heterotrimeric guanine nucleotide-binding proteins. SUMMARY OF THE DISCLOSURE To address the above identified limitations in the art, this disclosure provides methods of treating autoimmune disease, inflammatory disease, and / or aberrant immune responses, including asthma, or eliciting an anti-inflammatory response in a subject in need thereof. In yet another aspect, provided herein are methods of inhibiting the proliferation of TRM cells in a subject. In yet another aspect, provided herein are methods of inhibiting the development of stem-like TRM cells in a subject. In some aspects, the methods comprise, consist 1 4914-9544-4227.1 Atty Docket No.116639-2730 of, or consist essentially of modulating the expression of G Protein-Coupled Receptor 25 (GPR25) in the patient. In some aspects, the methods comprise, consist of, or consist essentially of administering to the subject an effective amount of an agent to inhibit the activity of a population of T-cells expressing GPR25, thereby treating the one or more of asthma, the autoimmune disease, or fibrotic disease in the subject. In yet another aspect, the methods comprise, consist of, or consist essentially of administering to the subject an effective amount of an agent that reduces expression of GPR25 in T-cells, thereby treating the one or more of asthma, the autoimmune disease, or the fibrotic disease in the subject. In some aspects, the T cells comprise, consist of, or consist essentially of CD4+ or CD8+ T-cells. In some aspects, the T cells comprise, consist of, or consist essentially of CD8+ T-cells. In some aspects, the T cells comprise, consist of, or consist essentially of tissue resident memory (TRM) cells. In some aspects, the agent comprises, consists of, or consists essentially of a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA. In some aspects, the siRNA or miRNA is complementary to at least a fragment of a polynucleotide encoding GPR25. In some aspects, administration of the agent induces lower than baseline expression of GPR25 in the T cells. In some aspects, higher than baseline expression is at least about a 2-fold increase in expression of the one or more genes relative to baseline expression and / or lower than baseline expression is at least about a 2-fold decrease in expression of the one or more genes relative to baseline expression. In some aspects, baseline expression comprises, consists of, or consists essentially of normalized mean gene expression. In some aspects, the methods further comprise, consist of, or consist essentially of, administering to the subject an additional therapy for the one or more of asthma, the autoimmune disease, or the fibrotic disease. In some aspects, the additional therapy comprises, consists of, or consists essentially of one or more of bronchodilators, corticosteroids, and / or monoclonal antibodies for the treatment of one or more of asthma, the autoimmune, or the fibrotic disease. 2 4914-9544-4227.1 Atty Docket No.116639-2730 In yet another aspect, provided herein is a method of diagnosing one or more of asthma, an autoimmune disease, or a fibrotic disease in a subject, comprising, consisting of, or consisting essentially of contacting a sample isolated from the subject with an agent that detects the presence of GPR25 in the sample isolated from the subject, wherein the presence of the one or more genes at higher than baseline expression levels is a diagnostic indicator of asthma or the autoimmune or the fibrotic disease or wherein the absence of the one or more genes at higher or lower than baseline expression levels is not diagnostic indicator of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In some aspects, the sample comprises, consists of, or consists essentially of a TRM cell. In yet another aspect, provided herein is a method of diagnosing one or more of asthma, an autoimmune disease, or a fibrotic disease in a subject comprising, consisting of, or consisting essentially of contacting tissue-resident memory cells (TRMs) isolated from the subject or a sample isolated from the subject, with an antibody or agent that recognizes and binds to GPR25 to determine the frequency of TRMs expressing these proteins, wherein a high frequency of TRMs expressing these proteins is diagnostic of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of determining the density of tissue-resident memory cells (TRMs) in a sample isolated from a subject comprising, consisting of, or consisting essentially of measuring expression of GPR25 genes in the sample, wherein higher than baseline expression of the GPR25 indicates higher density of TRMs in the sample. In yet another aspect, provided herein is a method of determining prognosis of a subject having a one or more of asthma, an autoimmune disease, or a fibrotic disease comprising, consisting of, or consisting essentially of measuring the density of tissue-resident memory cells (TRM) in a sample isolated from the subject, wherein a low density of TRM indicates a more positive prognosis or wherein a high density of TRM indicates a more negative prognosis, optionally wherein the more negative prognosis comprises a decreased probability in the reduction of symptoms of asthma, the autoimmune, or the fibrotic disease and a lack of low density TRM indicates a more positive prognosis. In some aspects, there is an increased probability in the 3 4914-9544-4227.1 Atty Docket No.116639-2730 reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of determining prognosis of a subject suffering from one or more of asthma, an autoimmune disease, or a fibrotic disease comprising, consisting of, or consisting essentially of contacting tissue-resident memory cells (TRMs) isolated from the subject with one or more of: an antibody or agent that recognizes and a protein encoded by a GPR25 gene, wherein a low density of TRMs indicates a more positive prognosis or wherein a high density of TRMs indicates a more negative prognosis. In some aspects, the more negative prognosis comprises a decreased probability in the reduction of symptoms of asthma, the autoimmune or the fibrotic disease, and wherein the more positive prognosis comprises an increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of determining prognosis of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease comprising, consisting of, or consisting essentially of contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds a protein encoded by a GPR25 gene to determine the frequency of TRMs expressing these proteins, wherein a low density of TRMs indicates a more positive prognosis or wherein a high density of TRMs indicates a more negative prognosis. In some aspects, the more negative prognosis comprises a decreased probability in the reduction of symptoms of the autoimmune or fibrotic disease, and wherein the more positive prognosis comprises an increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of determining prognosis of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease comprising contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds CD103 to determine the frequency of CD103+ TRMs or an antibody that recognizes and binds a protein encoded by a GPR25 gene to determine the frequency of TRMs expressing the protein, wherein a low density of TRMs indicates a more positive prognosis or wherein a high density of TRMs indicates a more negative prognosis, 4 4914-9544-4227.1 Atty Docket No.116639-2730 optionally wherein the more negative prognosis comprises a decreased probability in the reduction of symptoms of asthma, the autoimmune disease, or the fibrotic disease, and wherein the more positive prognosis comprises an increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of determining the responsiveness of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease to immunotherapy comprising, consisting of, or consisting essentially of contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds a protein encoded by a GPR25 gene to determine the frequency of TRMs in the subject, wherein a high frequency of TRMs indicates lack of responsiveness to immunotherapy. In yet another aspect, provided herein is a method of determining the responsiveness of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease to immunotherapy comprising, consisting of, or consisting essentially of contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds a protein encoded by a GPR25 gene and, to determine the frequency of TRMs expressing these proteins, wherein a low frequency of TRMs expressing these proteins indicates responsiveness to immunotherapy. In yet another aspect, provided herein is a method of determining prognosis of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease comprising, consisting of, or consisting essentially of measuring the density of CD103 or a protein encoded by a GPR25 gene in a sample isolated from the subject, wherein a low density of TRM indicates a more positive prognosis or wherein a high density or TRM indicates a more negative prognosis. In some another, the more negative prognosis comprises, consists of, or consists essentially a decreased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In some aspects the lack of low density TRM indicates a more positive prognosis. In some aspects, the more negative prognosis comprises, consists of, or consists essentially of the increased probability reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. 5 4914-9544-4227.1 Atty Docket No.116639-2730 In yet another aspect, provided herein is a method of identifying a subject that will or is likely to respond to one or more of an asthma therapy, an autoimmune therapy, or a fibrotic disease therapy, comprising, consisting of, or consisting essentially of contacting a sample isolated from the subject with an agent that detects the presence of GPR25 in the sample, wherein the presence of the one or more genes at higher or lower than baseline expression levels indicates that the subject is likely to respond to the one or more of the asthma therapy, the autoimmune therapy, or the fibrotic disease therapy. In some aspects, baseline expression comprises, consists of, or consists essentially of normalized mean gene expression. In some aspects, higher than baseline expression of the one or more genes is at least about a 2-fold increase in expression relative to baseline expression and / or lower than baseline expression of the one or more genes is at least about a 2-fold decrease in expression relative to baseline expression. In some aspects, the methods further comprise, consist of, or consist essentially of administering to a patient in need thereof an asthma therapy, an autoimmune therapy, or a fibrotic disease therapy to the subject. In some aspects, the asthma therapy, the autoimmune therapy, or the fibrotic disease therapy comprises, consists of, or consists essentially of one or more of hormonal therapy, immunotherapy, bronchodilators, corticosteroids, or monoclonal antibodies. In some aspects, the sample is contacted with an agent. In some aspects, the agent comprises, consists of, or consists essentially of a detectable lab or tag. In some aspects, the detectable label or tag comprises, consists of, or consists essentially of a radioisotope, a metal, horseradish peroxidase, alkaline phosphatase, avidin or biotin. In yet another aspect, the agent comprises, consists of, or consists essentially of comprises a polypeptide that binds to an expression product encoded by the gene, or a polynucleotide that hybridizes to a nucleic acid sequence encoding all or a portion of the gene. In some aspects, the antibody comprises, consists of, or consists essentially of an IgG, IgA, IgM, IgE or IgD, or a subclass thereof. In some aspects, the IgG comprises, consists of, or consists essentially of IgG1, IgG2, IgG3 or IgG4. In some aspects, the antigen binding fragment comprises, consists of, or consists essentially of a Fab, Fab’, F(ab’)2, Fv, Fd, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv) or VL or VH. 6 4914-9544-4227.1 Atty Docket No.116639-2730 In some aspects, the agent is contacted with the sample in conditions favoring binding of the agent to GPR25. In some aspects of the methods disclosed herein, the agent is contacted with the sample in conditions favoring binding of the agent to GPR25. In some aspects, the methods comprise, consist of, or consist essentially of detection by immunohistochemistry (IHC), in-situ hybridization (ISH), ELISA, immunoprecipitation, immunofluorescence, chemiluminescence, radioactivity, X-ray, nucleic acid hybridization, protein-protein interaction, immunoprecipitation, flow cytometry, Western blotting, polymerase chain reaction, DNA transcription, Northern blotting and / or Southern blotting. In some aspects, the sample comprises, consists of, or consists essentially of cells, tissue, an organ biopsy, an epithelial tissue, a lung, respiratory or airway tissue or organ, a circulatory tissue or organ, a skin tissue, bone tissue, muscle tissue, head, neck, brain, skin, bone and / or blood sample. In some aspects, the one or more of the asthma or autoimmune disease, or fibrotic disease comprises, consists of, or consists essentially of polymyositis, vasculitis syndrome, giant cell arteritis, Takayasu arteritis, relapsing, polychondritis, acquired hemophilia A, Still's disease, adult-onset Still's disease, amyloid A amyloidosis, polymyalgia rheumatic, Spondyloarthritides, Pulmonary arterial hypertension, graft-versus-host disease, autoimmune myocarditis, contact hypersensitivity (contact dermatitis), gastro-esophageal reflux disease, erythroderma, Behcet's disease, amyotrophic lateral sclerosis, transplantation, rheumatoid arthritis, juvenile rheumatoid arthritis, malignant rheumatoid arthritis, Drug-Resistant Rheumatoid Arthritis, Neuromyelitis optica, Kawasaki disease, polyarticular or systemic juvenile idiopathic arthritis, psoriasis, nonalcoholic fatty liver disease, primary biliary cholangitis, autoimmune hepatitis, autoimmune kidney disease, chronic obstructive pulmonary disease (COPD), Castleman’s disease, asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic encephalomyelitis, arthritis, arthritis chronica progrediente, reactive arthritis, psoriatic arthritis, enterophathic arthritis, arthritis deformans, rheumatic diseases, spondyloarthropathies, ankylosing spondylitis, Reiter syndrome, hypersensitivity (including both airway 7 4914-9544-4227.1 Atty Docket No.116639-2730 hypersensitivity and dermal hypersensitivity), allergies, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, erythema nodosum leprosum, Sjögren’s Syndrome, inflammatory muscle disorders, polychondritis, Wegener's granulomatosis, dermatomyositis, Steven-Johnson syndrome, chronic active hepatitis, myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, Irritable Bowel Syndrome, endocrine ophthalmopathy, scleroderma, Grave’s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, vaginitis, proctitis, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, juvenile diabetes (diabetes mellitus type I), autoimmune haematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia (ITP), autoimmune uveitis, uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, glomerulonephritis (with and without nephrotic syndrome), idiopathic nephrotic syndrome or minimal change nephropathy, inflammatory disease of skin, cornea inflammation, myositis, loosening of bone implants, metabolic disorder, atherosclerosis, dislipidemia, bone loss, osteoarthritis, osteoporosis, periodontal disease of obstructive or inflammatory airways diseases, bronchitis, pneumoconiosis, pulmonary emphysema, acute and hyperacute inflammatory reactions, acute infections, septic shock, endotoxic shock, adult respiratory distress syndrome, meningitis, pneumonia, cachexia wasting syndrome, stroke, herpetic stromal keratitis, dry eye disease, iritis, conjunctivitis, keratoconjunctivitis, Guillain-Barre syndrome, Stiff-man syndrome, Hashimoto's thyroiditis, autoimmune thyroiditis, encephalomyelitis, acute rheumatic fever, sympathetic ophthalmia, Goodpasture’s syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome, Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, atopic dermatitis, eczematous dermatitis, aphthous ulcer, lichen planus, autoimmune alopecia, Vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, sensorineural hearing loss, idiopathic bilateral progressive sensorineural hearing loss, autoimmune polyglandular syndrome type I or type II, immune infertility and immune-mediated infertility. BRIEF DESCRIPTION OF THE DRAWINGS FIGS.1A – 1D: TGF-β induces expression of GPR25 in CD8+T cells. (FIG. 1A), Quantitative real-time PCR (qRT-PCR) analysis of GPR25 expression levels in naïve 8 4914-9544-4227.1 Atty Docket No.116639-2730 human CD8+T cells stimulated with anti-CD3 and anti-CD28 in the presence or absence of TGF-β for 24 and 48 hours. (FIG.1B), UCSC genome browser tracks for genes in the extended GPR25 locus (50 kb), ATAC-seq tracks in the indicated CD8+T cell populations (top) and ENCODE chromatin immunoprecipitation sequencing tracks for NFATC1, NFATC3 and SMAD1 (bottom); C1, C2 and C3 cis-regulatory regions are shaded. (FIG.1C), Gpr25 expression levels in naïve murine CD8+T (CD8+CD44loCD62Lhi) stimulated with anti-CD3 and anti-CD28 in the presence or absence of TGF-β at the indicated time points. (FIG.1D), Gpr25 expression levels in CD8β+T cells (spleen), CD8β+CD69+and CD8β+CD69−T cells (liver), CD8α+CD8α+and CD8α+CD8β+T cells (siIEL) isolated from unmanipulated wild-type C57BL / 6J mice (>90 days old). Graphs in (FIG.1A), and (FIG.1D) depict mean ± S.E.M.; graphs in (FIG.1A), and (FIG.1D) depict mean ± S.D.; all data are representative of two independent experiments, with n = 5-11 in each experiment. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05, **P < 0.01 and **** P < 0.0001. 2A – 2E: Gpr25 promotes the development of liver TRMcells. (FIG. 2A), Illustration of the TRM model in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). (FIGS.2B – 2C), Flow-cytometric analysis of CD8+T cells isolated from the spleen, liver, and small intestinal intraepithelial lymphocytes (siIEL) of recipient mice (n = 8) at 90 days post infection. (FIG.2B), Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells are shown. (FIG.2C), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells that express CD69 and CXCR6, CD69 and CD103 are shown. (FIG.2D), Illustration of parabiosis experimental workflow. Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 (host) mice before infection with LCMV-OVA (i.p.). Thirty days post infection, anti-Gr1 were administrated as previous described25to eliminate circulating lymphocytes. Seven days after anti-Gr1 administration, CD8KO (recipient) mice were co-joined with CD45.1 mice (host) via parabiosis surgery. Mice were analyzed 30 days after the surgery. (FIG.2E), Flow-cytometric analysis of CD8+T cells isolated from the liver of host mice and spleen of recipient mice at 30 days after 9 4914-9544-4227.1 Atty Docket No.116639-2730 parabiosis surgery. Representative contour plots and frequencies of transferred Gpr25+ / +(WT; CD45.1.2), Gpr25- / -(KO; CD45.2) OT-I CD8+T cells from the liver of host CD45.1 mice and spleen of recipient mice are shown. Bar graphs in (FIGS.2B – 2C, FIG.2E) depict mean, each symbol represents data from an individual mouse; all data from (FIGS.2B – 2C) are representative of three independent experiments; data from (FIG.2E) are pooled data from two independent experiments. Statistical significance for the comparisons was computed using two- tailed two unequal variance Student t test; *P < 0.05, **P < 0.01 and *** P < 0.001. FIGS.3A – 3E: Gpr25 deficiency impairs early stages of TRMcell development. (FIG.3A), Illustration of the TRMmodel in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). (FIGS.3B – 3E), Flow- cytometric analysis of CD8+T cells isolated from the liver of recipient mice (n = 4) at 24 hours, 48 hours, days 5, 12 and 30 post infection. (FIG.3B), For the in vivo T cell proliferation assay, CTV-labeled OT-I cells were adoptively transferred into recipient mice before infection. Representative histogram and frequencies of proliferating OT-I cells are shown. (FIG.3C), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells that express CD69 and KLRG1 are shown for the indicated time point post infection. (FIG.3D), Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells are shown. (FIG.3E), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells that express CD69 and CXCR6 in the spleen and liver are shown; numbers adjacent to outlined areas indicate frequencies of cells co-expressing CD69 and CXCR6. Bar graphs in (FIGS.3B – 3E) depict mean, each symbol represents data from an individual mouse; all data from (FIGS.3B – 3E) are representative of three independent experiments. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05 and **P < 0.01. FIGS.4A – 4K: Gpr25 promotes the development of secondary TRMcells. (FIG.4A), (FIG.4B), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). Single-cell RNA-seq was performed on Gpr25+ / +(WT; 10 4914-9544-4227.1 Atty Docket No.116639-2730 CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRM cells (CD69+CD62L-KLRG1-) isolated from CD8+T cells in the liver of recipient mice (n = 8) at 30 days post infection. (FIG.4A), Volcano plot shows false discovery rate (FDR) and fold change in expression levels of differentially expressed transcripts (False discovery rate (FDR) ≤ 0.05, fold change > 0.25) between Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRMcells; dashed lines depict the threshold used for fold change and FDR; full list of differentially expressed transcripts is provided in Table 1. (FIG.4B), Gene- set enrichment analysis (GSEA) plot shows enrichment of the indicated gene signatures when comparing Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRM cells. False discovery rate (FDR) and normalized enrichment score (NES) were determined using fgsea package on R. (FIG.4C), Quantitative real-time PCR (qRT-PCR) analysis of Tcf7 expression levels and (FIG.4D) mean fluorescence intensity (MFI) of TCF1 in Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRMcells in the liver 30 days post infection. (FIG.4E), Illustration of the secondary TRM model in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRMcells, generated as described in Fig.3a, were isolated from liver and co-transferred at a 1:1 ratio into CD45.1 naïve recipient mice before infection with LCMV-OVA (i.p.). (FIGS.4F – 4H), Flow- cytometric analysis of CD8+T cells isolated from the liver of recipient mice (n = 4) at 30 days post infection. (FIG.4F), Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I T cells in the liver are shown. (FIG. 4G) (FIG.4H), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRM cells in the liver that express CD69 and CXCR6 (FIG.4G), CD69 and KLRG1 (FIG.4H) are shown; numbers adjacent to outlined areas (FIG.4G) indicate percentage of cells co-expressing CD69 and CXCR6. (FIG.4I), GSEA plot shows positive enrichment of TGF-β response gene signatures, from the indicated source, in Gpr25+ / +(WT) OT-I when compared to Gpr25- / -(KO) OT-I TRMcells. (FIG.4J), Flow-cytometric analysis naïve murine CD8+T cells (CD8+CD44loCD62Lhi) from Gpr25+ / +(WT) and Gpr25- / -(KO) mice stimulated with anti-CD3 and anti-CD28 in the presence or absence of TGF-β for 24 hours. Representative histogram plots showing phosphorylation of Smad2(pS465 / pS467) / Smad3(pS423 / pS425) in the indicated samples. (FIG.4K), Flow-cytometric analysis of naïve murine CD8+T cells (CD8+CD44loCD62Lhi) that were stimulated with anti-CD3 and anti-CD28 for 24h before transfection with pCMV-Thy1.1 (empty vector; EV) or pCMV-Gpr25-Thy1.1 (Gpr25), and then stimulated with TGF-β for 24 hours. Representative histogram plots showing phosphorylation of 11 4914-9544-4227.1 Atty Docket No.116639-2730 Smad2 / Smad3 in the indicated samples. Bar graphs in (FIGS.4F – 4H, FIGS.4J – 4K) depict mean, each symbol represents data from an individual mouse; all data from (FIGS.4F – 4H, FIGS.4J – 4K) are representative of two independent experiments. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001. FIGS.5A – 5H: Gpr25 promotes development of lung TRMcells. (FIG.5A), Illustration of the lung TRMmodel in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred intratracheally at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA delivered intratracheally (i.t.) (FIG. 5B), (FIG.5C), Flow-cytometric analysis of cells isolated from lungs of recipient mice (n = 5) at 30 days post infection. (FIG.5B), Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells in lungs are shown. (FIG.5C), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) OT-I CD8+T cells, Gpr25- / -(KO) OT-I CD8+T cells and host CD8+T cells that express CD69 and CD103 (top), CD69 and CXCR6 (bottom) are shown; numbers adjacent to outlined areas (bottom) indicate frequencies of cells co-expressing CD69 and CXCR6. (FIGS.5D – 5F), Single-cell RNA-seq analysis of Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells isolated from lungs of recipient mice (n = 6) at 30 days post infection. (FIG.5D), Single-cell transcriptomes of Gpr25+ / +(WT; top) and Gpr25- / -(KO; bottom) OT-I CD8+T cells are displayed by uniform manifold approximation and projection (UMAP), using equal cell numbers for each group (n = 706). Seurat-based clustering of 2,102 cells colored based in cluster type; the proportion of cells each cluster is shown (right). (FIG.5E), Plot shows Z-score average expression and percentage of cells (size scale) expressing selected transcripts that are differentially expressed in the two clusters (FDR ≤ 0.05, fold change > 0.25). (FIG.5F), UMAPs illustrating Seurat-normalized expression levels of Il7r, Xcl1, Gpr183, Zeb2, S1pr5, Gzmb, and Cx3cr1 transcripts in single cells. (FIG.5G), Illustration of the lung TRM model in which Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells were transferred into independent cohorts of CD8KO recipient mice before infection with LCMV-OVA (i.t.). (FIG.5H), Representative histograms and the frequencies of TCF1-expressing cells in Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells. Bar graphs in (FIGS.5B – 5C) depict mean, bar graphs in (FIG.5H) depict mean ± S.D.; each symbol represents data from an individual mouse; all data from (FIG.5B), 12 4914-9544-4227.1 Atty Docket No.116639-2730 (FIG.5C) are representative of three independent experiments. Data from (FIG.5H) are representative of two independent experiments. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; **P < 0.01. FIGS.6A – 6G: Gpr25-deficient T cells fail to control lung metastasis. (FIG. 6A), Illustration of the lung metastasis model in which Gpr25+ / +(WT; CD45.1.2) OT-I CD8+T cells were transferred intratracheally (OT-I transfer group) into CD45.1 recipient mice before infection with LCMV-OVA (i.t.); Thirty days after infection, B16F10-OVA melanoma cells were injected intravenously. To compare with endogenous anti-tumor immune responses, a group of mice did not receive OT-I cells or LCMV-OVA infection (no transfer group). (FIG. 6B), Representative picture of lung metastatic nodules and number of nodules on the surface of 5 lobes assessed 13 days after tumor injection in mice from the OT-I transfer and no transfer group. (FIG.6A), Illustration of the lung metastasis model in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred intratracheally at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.t.); Thirty days after infection, B16F10-OVA melanoma cells were injected intravenously into these mice. (FIG.6B), Flow-cytometric analysis of CD8+T cells isolated from the lungs of recipient mice (n = 4) at 13 days after tumor injection. Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells are shown. (FIG.6C), (FIG.6E), Illustration of the lung metastasis model in which Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells were transferred intratracheally into two cohorts of (FIG.6C) CD45.1 or (FIG.6E) CD8KO recipient mice before infection with LCMV-OVA (i.t.). Thirty days after infection, B16F10-OVA melanoma cells were injected intravenously into these mice and FTY720 was intraperitoneally administrated to mice at indicated time points. (FIG.6D), Representative picture of lung metastatic nodules and number of nodules on the surface of 5 lobes, assessed 14 days after tumor injection, in the mice receiving Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells. (FIG.6F), Survival curve of cohorts of CD8KO recipient mice that received Gpr25+ / +(WT), Gpr25- / -(KO) OT-I CD8+T cells or no adoptive transfer of OT-1 CD8+T cells. (FIG.6G), Representative picture of lung metastatic nodules and number of nodules on the surface of 5 lobes, assessed 14 days after tumor injection, in mice from the OT-I transfer and no OT-1 transfer group. Bar graph in (FIG.6B) depicts mean, graphs in (FIG.6D), (FIG.6G) depict mean ± S.D., each symbol represents data from an individual 13 4914-9544-4227.1 Atty Docket No.116639-2730 mouse; all data from (FIG.6B) are representative of two independent experiments. Data from (FIG.6F), (FIG.6G) are pooled data from two independent experiments. Statistical significance for the comparisons in (FIG.6B), (FIG.6D), (FIG.6G) was computed using two-tailed two unequal variance Student t test; *P < 0.05, **P < 0.01 and ***P < 0.001. Statistical significance for the comparisons in (FIG.6F), was calculated using Kaplan-Meier test; *P < 0.0332. FIGS.7A – 7B: Sequence analysis of GPR25 and flow cytometry gating strategies. (FIG.7A), Alignment of human and mouse GPR25 (Genebank entries NP_005289.2, NP_001094986.1, respectively). Identical amino acid residues are shown as (*), homology as (:), and different residues shaded. Predicted transmembrane domain (TM helix) regions are indicated by the lines above the amino acid labels. (FIG.7B), Flow-cytometric plots show sequential gating strategies for isolating CD8+CD69+and CD8+CD69−T cells present in spleen and liver (top panel), CD8α+CD8α+and CD8α+CD8β+T cells present in small intestinal intraepithelial lymphocytes (siIEL; bottom panel) of unmanipulated wild-type C57BL / 6J mice (> 90 days old), used in FIG.1D. FIGS.8A – 8E: Gpr25 promotes the development of liver TRMcells. (FIGS. 8A – 8C), Illustration of the TRM model in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). OT-I TRMcells (CD69+CD62L-KLRG1- ) were sorted from CD8+T cells isolated from liver, OT-I TEM (CD127+CD62L-) and OT-I TCM (CD127+CD62L+) cells were sorted from CD8+T cells isolated from spleen of recipient mice (n= 6) at 30 days post infection. (FIG.8B), Representative contour plots show expression of CD69 and CD62L in OT-I cells. c, Quantitative real-time PCR (qRT-PCR) analysis of Gpr25 (left) and S1pr1 (right) expression levels in the indicated T cell subsets from Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells. (FIG.8D), (FIG.8E), Congenically distinct Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). Flow-cytometric analysis of CD8+T cells isolated from the liver and small intestinal intraepithelial lymphocytes (siIEL) of recipient mice at 90 days post infection; gating strategy for phenotyping transferred OT-I cells is shown in (FIG.8D). (FIG.8E), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells that express CD69 and CXCR6, CD69 and 14 4914-9544-4227.1 Atty Docket No.116639-2730 CD103 are shown for n = 6 mice (independent repeat of experiment shown in FIG.2D); numbers adjacent to outlined areas (FIG.8D) indicate frequencies of cells co-expressing CD69 and CXCR6. Bar graph in (FIG.8C) depicts mean ± S.E.M., bar graph in (FIG.8E) depicts mean, each symbol represents data from an individual mouse. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05, **P < 0.01 and ***P < 0.001. FIGS.9A – 9D: Gpr25 deficiency impairs early stages of TRMcell development. (FIGS.9A – 9D), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). Flow-cytometric analysis of CD8+T cells isolated from the liver of recipient mice (n= 5) at 24 hours, 48 hours, day 30 post infection. (FIG.9A), Frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells in liver at 24 and 48 hours post infection are shown. (FIG. 9B), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells that express CD66 and CD44 in liver at 24 and 48 hours are shown. (FIG.9C), Mean fluorescence intensity of CD25 expression in transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells at 24 hours post infection is shown. (FIG.9D), Representative contour plots show frequency of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells in liver that express CD69, CD62L, CD44 and CD127 at 30 days post infection. Bar graphs in a-c depicts mean, each symbol represents data from an individual mouse. FIGS.10A – 10D: Gpr25 promotes the development of secondary TRMcells. (FIG.10A), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). Single-cell RNA-seq was performed on Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRM cells (CD69+CD62L- KLRG1-) isolated from CD8+T cells in the liver of recipient mice (n= 8) at 30 days post infection. Expression levels of the indicated transcripts in Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRM cells are shown. (FIG.10B), (FIG. 10D), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV- OVA (i.p.). Single-cell RNA-seq was performed on total Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I T cells isolated from liver of recipient mice (n= 8) at 12 days post infection. (FIG.10B), Gene-set enrichment analysis (GSEA) plot shows enrichment of the indicated gene 15 4914-9544-4227.1 Atty Docket No.116639-2730 signatures in Gpr25+ / +(WT) when compared to Gpr25- / -(KO) T cells. False discovery rate (FDR) and normalized enrichment score (NES) were determined using fgsea package on R. (FIG.10C), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRMcells, generated as described in FIG.3A, were isolated from liver and co-transferred at a 1:1 ratio into CD45.1 naïve recipient mice before infection with LCMV-OVA (i.p.). Flow- cytometric analysis of CD8+T cells isolated from the liver of recipient mice (n= 4) at 30 days post infection. Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRM cells in the liver that express CD69 and CD62L are shown. (FIG.10D), GSEA plot shows positive enrichment of TGF-β response gene signatures, from the indicated source, in Gpr25+ / +(WT) OT-I when compared to Gpr25- / -(KO) OT-I T cells isolated from the liver 12 days post infection. False discovery rate (FDR) and normalized enrichment score (NES) were determined using fgsea package on R. Bar graph depicts mean, each symbol represents data from an individual mouse; all data are representative of two independent experiments, with n = 4 mice in each experiment. Statistical significance for the comparisons was computed using two- tailed two unequal variance Student t test; ***P < 0.001. FIGS.11A – 11E: Gpr25 promotes development of lung TRMcells. (FIG.11A), Illustration of the TRMmodel in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred intravenously at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA delivered intraperitoneally (i.p.) (FIGS.11B – 11C), Flow-cytometric analysis of cells isolated from lungs of recipient mice at 30 days (n = 5) and 120 days (n = 3) post infection. (FIG.11B), Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells in the lungs are shown. (FIG.11C), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) OT-I CD8+T cells, Gpr25- / -(KO) OT-I CD8+T cells and host CD8+T cells in the lungs that express CD69 and CD103 are shown. (FIG.11D), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred intratracheally at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA delivered intratracheally (i.t.). Flow-cytometric analysis of cells isolated from lungs of recipient mice (n = 6) at 30 days post infection. Representative contour plots and frequencies of transferred Gpr25+ / +(WT) OT-I CD8+T cells, Gpr25- / -(KO) OT-I CD8+T cells and host CD8+T cells that express CD69 and CD103 are shown (independent repeat of experiment shown in FIGS.5A – 5C). (FIG.11E), Single-cell RNA-seq analysis of Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells isolated from lungs of recipient mice (n = 6) at 30 days post infection. UMAPs illustrating 16 4914-9544-4227.1 Atty Docket No.116639-2730 Seurat-normalized expression levels of Cd27, Fasl, Gzma, Prf1 and Klrg1 transcripts in single cells. Bar graphs in (FIGS.11B – 11D) depict mean, each symbol from (FIGS.11B – 11D) represents data from an individual mouse. all data from (FIGS.11B – 11D) are representative of three independent experiments, with n = 3-6 mice in each experiment. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05. FIGS.12A – 12C: Gpr25-deficient T cells fail to control lung metastasis. (FIG.12A), Illustration of the lung metastasis model. Gpr25+ / +(WT; CD45.1.2) OT-I CD8+T cells were transferred intratracheally (OT-I transfer group) into CD45.1 recipient mice before infection with LCMV-OVA (i.t.); Thirty days after infection, B16F10-OVA melanoma cells were injected intravenously. FTY720 or control PBS was intraperitoneally administrated to mice at indicated time points. (FIG.12B), Picture of lung metastatic nodules and number of nodules assessed 13 days after tumor injection. (FIG.12C), Representative contour plots and frequencies of total CD8+T cells in the tumors of mice from the indicated groups. Bar graphs in (FIG.12B) depicts mean, graph in (FIG.12C) depict mean ± S.D.; each symbol represents data from an individual mouse; all data from (FIGS.12B – 12C) are representative of two independent experiments. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05, **P < 0.01. FIG.13. Ligand-Induced Forward Trafficking (LIFT) assay. Mutant oGPCR is retained in the ER. Chemical ligands that bind the target (1) facilitate transit from the ER through the Golgi (2) to the PM. Trafficking of the ligand:oGPCR complex to the PM leads to internalization via the early endosome (3), where the EA-tagged EEA1 protein resides. Internalization brings the PK and EA tags together to form a functional enzyme. Exogenously added substrate is converted to light (4). The split β-gal enzyme fragments, PK and EA are shown in light gray and dark gray respectively. LU : Light. FIG.14 illustrates a GPR25 Hit ID testing funnel. FIG.15 illustrates a GPR25 lead generation plan. FIG.16. Demonstrates quantitative real-time PCR (qRT-PCR) analysis of GPR25 expression levels in naïve human (left) and murine (right) CD8+ T cells stimulated with anti- CD3 and anti-CD28 in the presence or absence of TGF-β for 24 and 48 hours. Graphs depict 17 4914-9544-4227.1 Atty Docket No.116639-2730 mean ± S.E.M.; all data are representative of two independent experiments, with n = 5-11 in each experiment. Statistical significance was computed using two-tailed two unequal variance Student t test; *P < 0.05 and **P < 0.01. DETAILED DESCRIPTION OF THE DISCLOSURE Embodiments according to the present disclosure will be described more fully hereinafter. Aspects of the disclosure may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All nucleotide sequences provided herein are presented in the 5′ to 3′ direction. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, particular, non-limiting exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the disclosure is not entitled to antedate such disclosure by virtue of prior disclosure. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology and recombinant DNA, which are within the skill of the art. See, e.g., Sambrook and Russell eds, (2001) Molecular Cloning: A Laboratory Manual, 3rd edition; the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., N.Y.); MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach; Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual; Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5th edition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Pat. No.4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) 18 4914-9544-4227.1 Atty Docket No.116639-2730 Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds, (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); and Herzenberg et al. eds (1996) Weir's Handbook of Experimental Immunology. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The practice of the present technology will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the skill of the art. Unless the context indicates otherwise, it is specifically intended that the various features of the disclosure described herein can be used in any combination. Moreover, the disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination. Unless explicitly indicated otherwise, all specified embodiments, features, and terms intend to include both the recited embodiment, feature, or term and biological equivalents thereof. All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied ( + ) or ( - ) by increments of 1.0 or 0.1, as appropriate, or alternatively by a variation of + / - 15 %, or alternatively 10%, or alternatively 5%, or alternatively 2% and such ranges are included. It is to be understood, although not always explicitly stated, that all numerical designations are preceded 19 4914-9544-4227.1 Atty Docket No.116639-2730 by the term “about”. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art. Throughout this disclosure, various publications, patents and published patent specifications may be referenced by an identifying citation or by an Arabic numeral. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure in their entirety to more fully describe the state of the art to which this disclosure pertains. Definitions As used in the description of the disclosure and the appended claims, the singular “a,” “an” and “the” are intended to include the plural forms as well, unless the context indicates otherwise. As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but do not exclude others. As used herein, the transitional phrase consisting essentially of (and grammatical variants) is to be interpreted as encompassing the recited materials or steps and those that do not materially affect the basic and novel characteristic(s) of the recited embodiment. Thus, the term “consisting essentially of” as used herein should not be interpreted as equivalent to “comprising”. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions disclosed herein. Aspects defined by each of these transition terms are within the scope of the present disclosure. The term “about” as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. As used herein, the terms “increased”, “decreased”, “high”, “low” or any grammatical variation thereof refer to a variation of about 90%, 80%, 50%, 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the reference composition, polypeptide, protein, etc. 20 4914-9544-4227.1 Atty Docket No.116639-2730 The terms or “acceptable,” “effective,” or “sufficient” when used to describe the selection of any components, ranges, dose forms, etc. disclosed herein intend that said component, range, dose form, etc. is suitable for the disclosed purpose. Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). An equivalent of a polynucleotide (referred to herein as the reference) shares at least 50% (or at least 60%, or at least 70%, or at least 80%, or at least 90%) identity to the reference, and encodes the same polypeptide as the one encoded by the reference, or encodes an equivalent of the polypeptide encoded by the reference. To arrive at a position or a consecutive segment of a test sequence equivalent to (or corresponding to)an / a amino acid / nucleotide residue or a consecutive segment of a reference sequence, a sequence alignment is performed between the test and reference sequences. The positions or segments aligned to each other are determined as equivalents. The term “analogue” refers to an equivalent having one or more modified amino acids and one or more amino acids replaced with another amino acid. Such modification may include but is not limited to conjugation with a molecule (for example, a small molecule, a cytotoxic molecule, a linker, a pH-sensitive linker, and / or a thiol linker), sialylation, polysialylation, O-glycosylation, N-glycosylation, myristoylation, palmitoylation, isoprenylation or prenylation, glipyatyon, lipoylation, phosphopantetheinylation, ethanolamine phosphoglycerol attachment, diphthamide formation, hypusine formation, acylation, acetylation, formylation, alkylation, methylation, amidation, citrullination, deamidation, eliminylation, ISGylation, SUMOylation, ubiquitination, neddylation, pupylation, biotinylation, carbamylation, oxidation, pegylation, glycation, carbamylation, carbonylation, spontaneous isopeptide bond formation, butyrylation, gamma-carboxylation, malonylation, hydroxylation, iodination, nucleotide addition, phosphate ester (O-linked) or phosphoramidate (N-linked) formation, phosphorylation, adenylylation, uridylylation, propionylation, pyroglutamate formation, S-glutathionylation, S- nitrosylation, S-sulfenylation, S-sulfinylation, S-sulfonylation, succinylation, and / or sulfation. The term “albumin equivalent,” comprises, or consists essentially of, or yet further consists of, 21 4914-9544-4227.1 Atty Docket No.116639-2730 polypeptides which can be expressed at a reasonable quantity and which still retains or improves on certain albumin properties, including the binding of the albumin fragment to an FcRn receptor, as is known in the art or described herein. The term “affinity tag” refers to a polypeptide that may be included within a fusion protein to allow detection of the fusion protein and / or purification of the fusion protein from the cellular milieu using a ligand that is able to bind to, i.e., has affinity for, the affinity tag. The ligand may be, but is not limited to, an antibody, a resin, or a complementary polypeptide. An affinity tag may comprise a small peptide, commonly a peptide of approximately 4 to 16 amino acids in length, or it may comprise a larger polypeptide. Commonly used affinity tags include polyarginine, FLAG, V5, polyhistidine, c-Myc, Strep II, maltose binding protein (MBP), N-utilization substance protein A (NusA), thioredoxin (Trx), and glutathione S-transferase (GST), among others (for examples, see GST Gene Fusion System Handbook - Sigma-Aldrich). In an embodiment the affinity tag is a polyhistidine tag, for example a His6tag. The inclusion of an affinity tag in a fusion protein allows the fusion protein to be purified from the cellular milieu by affinity purification, using an affinity medium that is able to tightly and specifically bind the affinity tag. The affinity medium may comprise, for example, a metal-charged resin or a ligand covalently linked to a stationary phase (matrix) such as agarose or metal beads. For example, polyhistidine tagged fusion proteins (also referred to as His tagged fusion proteins) can be recovered by immobilized metal ion chromatography using Ni2+or Co2+loaded resins, anti- FLAG affinity gels may be used to capture FLAG tagged fusion proteins, and glutathione cross- linked to a solid support such as agarose may be used to capture GST tagged fusion proteins. As used herein the terms “purification”, “purifying”, or “separating” refer to the process of isolating one or more polypeptides from a complex mixture, such as a cell lysate or a mixture of polypeptides. The purification, separation, or isolation need not be complete, i.e., some components of the complex mixture may remain with the one or more polypeptides after the purification process. However, the product of purification should be enriched for the one or more polypeptides relative to the complex mixture before purification and a significant portion of the other components initially present within the complex mixture should be removed by the purification process. 22 4914-9544-4227.1 Atty Docket No.116639-2730 The term “cell” as used herein may refer to either a prokaryotic or eukaryotic cell, optionally obtained from a subject or a commercially available source. “Eukaryotic cells” comprise all of the life kingdoms except monera. They can be easily distinguished through a membrane-bound nucleus. Animals, plants, fungi, and protists are eukaryotes or organisms whose cells are organized into complex structures by internal membranes and a cytoskeleton. The most characteristic membrane-bound structure is the nucleus. Unless specifically recited, the term “host” includes a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells. Non-limiting examples of eukaryotic cells or hosts include simian, bovine, porcine, murine, rat, avian, reptilian and human, e.g., HEK293 cells, Chinese Hamster Ovary (CHO) cells and 293T cells. “Prokaryotic cells” that usually lack a nucleus or any other membrane-bound organelles and are divided into two domains, bacteria and archaea. In addition to chromosomal DNA, these cells can also contain genetic information in a circular loop called an episome. Bacterial cells are very small, roughly the size of an animal mitochondrion (about 1-2 μm in diameter and 10 μm long). Prokaryotic cells feature three major shapes: rod shaped, spherical, and spiral. Instead of going through elaborate replication processes like eukaryotes, bacterial cells divide by binary fission. Examples include but are not limited to Bacillus bacteria, E. coli bacterium, and Salmonella bacterium. The term “encode” as it is applied to nucleic acid sequences refers to a polynucleotide which is said to “encode” a polypeptide if, in its native state or when manipulated by methods well known to those skilled in the art, can be transcribed and / or translated to produce the mRNA for the polypeptide and / or a fragment thereof. The antisense strand is the complement of such a nucleic acid, and the encoding sequence can be deduced therefrom. As used herein, “expression” refers to the process by which polynucleotides are transcribed into mRNA and / or the process by which the transcribed mRNA is subsequently being translated into peptides, polypeptides, or proteins. If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell. 23 4914-9544-4227.1 Atty Docket No.116639-2730 In some aspects, baseline expression is assessed via immunohistochemistry or flow-cytometry of tissue biopsies (i.e. healthy adjacent tissue) and comprises, consists of, or consists essentially of normalized mean expression. In some aspects, expression of GPR25 will be measured in tumor biopsies and compared to baseline levels, where higher than baseline expression of GPR25 comprises, consists of, or consists essentially of at least about a 2 or more, or about 3, or about 4, or about 5, or about 6, or about 7, or about 8, or about 9, or about 10, or about 11, or about 12, or about 13, or about 14, or about 15 fold increase in expression relative to baseline expression and / or lower than baseline expression of GPR25 is at least about a 2 or more, or about 3, or about 4, or about 5, or about 6, or about 7, or about 8, or about 9, or about 10, or about 11, or about 12, or about 13, or about 14, or about 15 fold decrease in expression relative to baseline expression. The term “isolated” or a grammatical variation thereof as used herein refers to molecules or biologicals or cellular materials being substantially free from other materials. As used herein, the term “functional” may be used to modify any molecule, biological, or cellular material to intend that it accomplishes a particular, specified effect. As used herein, the terms “nucleic acid sequence” and “polynucleotide” are used interchangeably to refer to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides. Thus, this term includes, but is not limited to, single-, double-, or multi- stranded DNA or RNA, genomic DNA, complementary DNA (cDNA), DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. In certain embodiments, the polynucleotide comprises and / or encodes a messenger RNA (mRNA), a short hairpin RNA, and / or small hairpin RNA. In one embodiment, the polynucleotide is or encodes an mRNA. In certain embodiments, the polynucleotide is a double-strand (ds) DNA, such as an engineered ds DNA or a ds cDNA synthesized from a single-stranded RNA. The terms “polynucleotide” and “oligonucleotide” are used interchangeably and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides or analogs thereof. Polynucleotides can have any three-dimensional structure and may perform any function, known or unknown. The following are non-limiting examples of 24 4914-9544-4227.1 Atty Docket No.116639-2730 polynucleotides: a gene or gene fragment (for example, a probe, primer, EST or SAGE tag), exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, RNAi, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes and primers. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polynucleotide. The sequence of nucleotides can be interrupted by non- nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. The term also refers to both double- and single- stranded molecules. Unless otherwise specified or required, any embodiment disclosed herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form. A polynucleotide is composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide is RNA. Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. The term “isolated” or “recombinant” as used herein with respect to nucleic acids, such as DNA or RNA, refers to molecules separated from other DNAs or RNAs, respectively that are present in the natural source of the macromolecule as well as polypeptides. The term “isolated or recombinant nucleic acid” is meant to include nucleic acid fragments which are not naturally occurring as fragments and would not be found in the natural state. The term “isolated” is also used herein to refer to polynucleotides, polypeptides and proteins that are isolated from other cellular proteins and is meant to encompass both purified and recombinant polypeptides. In other embodiments, the term “isolated or recombinant” means separated from constituents, cellular and otherwise, in which the cell, tissue, polynucleotide, peptide, polypeptide, protein, antibody or fragment(s) thereof, which are normally associated in nature. For example, an isolated cell is a cell that is separated from tissue or cells of dissimilar phenotype or genotype. An isolated polynucleotide is separated from the 3′ and 5′ contiguous nucleotides with which it is 25 4914-9544-4227.1 Atty Docket No.116639-2730 normally associated in its native or natural environment, e.g., on the chromosome. As is apparent to those of skill in the art, a non-naturally occurring polynucleotide, peptide, polypeptide, protein, antibody or fragment(s) thereof, does not require “isolation” to distinguish it from its naturally occurring counterpart. As used herein, the terms “engineered” “synthetic” “recombinant” and “non- naturally occurring” are interchangeable and indicate intentional human manipulation, for example, a modification from its naturally occurring form, and / or a sequence optimization. The terms “equivalent” or “biological equivalent” are used interchangeably when referring to a particular molecule, biological, or cellular material and intend those having minimal homology while still maintaining desired structure or functionality (for example, having a similar functional activity). It should be understood, without being explicitly stated that when referring to an equivalent or biological equivalent to a reference polypeptide, protein, or polynucleotide , that an equivalent or biological equivalent has the recited structural relationship to the reference polypeptide, protein, or polynucleotide and equivalent or substantially equivalent biological activity. For example, non-limiting examples of equivalent polypeptides, proteins, or polynucleotides include a polypeptide, protein or polynucleotide having at least 60%, or alternatively at least 65%, or alternatively at least 70%, or alternatively at least 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95% identity thereto or for polypeptide, polynucleotide or protein sequences across the length of the reference polynucleotide. Alternatively, an equivalent polypeptide is one that is encoded by a polynucleotide or its complement that hybridizes under conditions of high stringency to a polynucleotide encoding such reference polypeptide sequences and that have substantially equivalent or equivalent biological activity. Conditions of high stringency are described herein and incorporated herein by reference. Alternatively, an equivalent thereof is a polypeptide encoded by a polynucleotide or a complement thereto, having at least 70%, or alternatively at least 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95% identity, or at least 97% sequence identity across the length of the reference polynucleotide to the reference polynucleotide, e.g., the wild-type polynucleotide. Such equivalent polypeptides have the same biological activity as the reference polynucleotide. 26 4914-9544-4227.1 Atty Docket No.116639-2730 Non-limiting examples of equivalent polypeptides, include a polynucleotide having at least 60%, or alternatively at least 65%, or alternatively at least 70%, or alternatively at least 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95%, or alternatively at least 97%, identity to a reference polynucleotide. An equivalent also intends a polynucleotide or its complement that hybridizes under conditions of high stringency to a reference polynucleotide. Such equivalent polypeptides have the same biological activity as the reference polynucleotide. A polynucleotide or polynucleotide region (or a polypeptide or polypeptide region) having a certain percentage (for example, 80%, 85%, 90%, or 95%) of “sequence identity” to another sequence means that, when aligned, that percentage of bases (or amino acids) are the same in comparing the two sequences across the length of the reference polynucleotide. The alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in Current Protocols in Molecular Biology (Ausubel et al., eds.1987) Supplement 30, section 7.7.18, Table 7.7.1.In certain embodiments, default parameters are used for alignment. A non-limiting exemplary alignment program is BLAST, using default parameters. In particular, exemplary programs include BLASTN and BLASTP, using the following default parameters: Genetic code=standard; filter=none; strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions=50 sequences; sort by=HIGH SCORE; Databases=non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov / cgi- bin / BLAST. Sequence identity and percent identity can be determined by incorporating them into clustalW (available at the web address:genome.jp / tools / clustalw / , last accessed on Jan.13, 2017). “Homology” or “identity” or “similarity” refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence that may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. An “unrelated” or “non- 27 4914-9544-4227.1 Atty Docket No.116639-2730 homologous” sequence shares less than 40% identity, or alternatively less than 25% identity, with one of the sequences of the present disclosure as determined using BLAST, using default parameters or BLASTN and BLASTP, using the following default parameters: Genetic code=standard; filter=none; strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions=50 sequences; sort by=HIGH SCORE; Databases=non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov / cgi- bin / BLAST. Sequence identity and percent identity can be determined by incorporating them into clustalW (available at the web address:genome.jp / tools / clustalw / , last accessed on Jan.13, 2017). As used herein, the term “at least 90% identical” refers to an identity of two compared sequences (polynucleotides or polypeptides) of about 90% to about 100%. It also include an identity of at least at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, about 91% to about 100%, about 92% to about 100%, about 93% to about 100%, about 94% to about 100%, about 95% to about 100%, about 96% to about 100%, about 97% to about 100%, about 98% to about 100%, or about 99% to about 100% as determined using BLAST, using default parameters or BLASTN and BLASTP, using the following default parameters: Genetic code=standard; filter=none; strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions=50 sequences; sort by=HIGH SCORE; Databases=non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov / cgi-bin / BLAST. Sequence identity and percent identity can be determined by incorporating them into clustalW (available at the web address:genome.jp / tools / clustalw / , last accessed on Jan.13, 2017). “Homology” or “identity” or “similarity” can also refer to two nucleic acid molecules that hybridize under stringent conditions. As used herein, the terms “retain” “similar” and “same” are used interchangeably while describing a function, an activity or an functional activity of a polynucleotide, a protein and / or a peptide, referring to a functional activity of at least about 20% (including but not limited 28 4914-9544-4227.1 Atty Docket No.116639-2730 to: at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or about 100%) of the activity of the reference protein, polynucleotide and / or peptide using methods disclosed herein. It is to be inferred without explicit recitation and unless otherwise intended, that when the present disclosure relates to a polypeptide, protein, polynucleotide or antibody, an equivalent or a biologically equivalent of such is intended within the scope of this disclosure. As used herein, the term “biological equivalent thereof” is intended to be synonymous with “equivalent thereof” when referring to a reference protein, antibody, fragment, polypeptide or nucleic acid, intends those having minimal homology while still maintaining desired structure or functionality. Unless specifically recited herein, it is contemplated that any polynucleotide, polypeptide or protein mentioned herein also includes equivalents thereof. In one aspect, an equivalent polynucleotide is one that hybridizes under stringent conditions to the polynucleotide or complement of the polynucleotide as described herein for use in the described methods. In another aspect, an equivalent antibody or antigen binding polypeptide intends one that binds with at least 70%, or alternatively at least 75%, or alternatively at least 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95% affinity or higher affinity to a reference antibody or antigen binding fragment. In another aspect, the equivalent thereof competes with the binding of the antibody or antigen binding fragment to its antigen under a competitive ELISA assay. In another aspect, an equivalent intends at least about 80% homology or identity and alternatively, at least about 85%, or alternatively at least about 90%, or alternatively at least about 95%, or alternatively 98% percent homology or identity and exhibits substantially equivalent biological activity to the reference protein, polypeptide or nucleic acid. As used herein, “oligonucleotide” refers to a molecule that has a sequence of nucleic acid bases on a backbone comprised mainly of identical monomer units at defined intervals. The bases are arranged on the backbone in such a way that they can bind with a nucleic acid having a sequence of bases that are complementary to the bases of the oligonucleotide. The most common oligonucleotides have a backbone of sugar phosphate units. A distinction may be made between oligodeoxyribonucleotides that do not have a hydroxyl group at the 2' position and oligoribonucleotides that have a hydroxyl group at the 2' position. 29 4914-9544-4227.1 Atty Docket No.116639-2730 Oligonucleotides may also include derivatives, in which the hydrogen of the hydroxyl group is replaced with organic groups, e.g., an allyl group. One or more bases of the oligonucleotide may also be modified to include a phosphorothioate bond (e.g., one of the two oxygen atoms in the phosphate backbone which is not involved in the internucleotide bridge, is replaced by a sulfur atom) to increase resistance to nuclease degradation. The exact size of the oligonucleotide will depend on many factors, which in turn depend on the ultimate function or use of the oligonucleotide. The oligonucleotide may be generated in any manner, including, for example, chemical synthesis, DNA replication, restriction endonuclease digestion of plasmids or phage DNA, reverse transcription, PCR, or a combination thereof. The oligonucleotide may be modified e.g., by addition of a methyl group, a biotin or digoxigenin moiety, a fluorescent tag or by using radioactive nucleotides. “Encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA. “Hybridization” refers to a reaction in which one or more polynucleotides react to form a complex that is stabilized via hydrogen bonding between the bases of the nucleotide residues. The hydrogen bonding may occur by Watson-Crick base pairing, Hoogstein binding, or in any other sequence-specific manner. The complex may comprise two strands forming a duplex structure, three or more strands forming a multi-stranded complex, a single self-hybridizing strand, or any combination of these. A hybridization reaction may constitute a step in a more extensive process, such as the initiation of a PCR reaction, or the enzymatic cleavage of a polynucleotide by a ribozyme. 30 4914-9544-4227.1 Atty Docket No.116639-2730 Examples of stringent hybridization conditions include: incubation temperatures of about 25° C. to about 37° C.; hybridization buffer concentrations of about 6×SSC to about 10×SSC; formamide concentrations of about 0% to about 25%; and wash solutions from about 4×SSC to about 8×SSC. Examples of moderate hybridization conditions include: incubation temperatures of about 40° C. to about 50° C.; buffer concentrations of about 9×SSC to about 2×SSC; formamide concentrations of about 30% to about 50%; and wash solutions of about 5×SSC to about 2×SSC. Examples of high stringency conditions include: incubation temperatures of about 55° C. to about 68° C.; buffer concentrations of about 1×SSC to about 0.1×SSC; formamide concentrations of about 55% to about 75%; and wash solutions of about 1×SSC, 0.1×SSC, or deionized water. In general, hybridization incubation times are from 5 minutes to 24 hours, with 1, 2, or more washing steps, and wash incubation times are about 1, 2, or 15 minutes. SSC is 0.15 M NaCl and 15 mM citrate buffer. It is understood that equivalents of SSC using other buffer systems can be employed. The term “protein”, “peptide” and “polypeptide” are used interchangeably and in their broadest sense to refer to a compound of two or more subunits of amino acids, amino acid analogs or peptidomimetics. The subunits may be linked by peptide bonds. In another aspect, the subunit may be linked by other bonds, e.g., ester, ether, etc. A protein or peptide must contain at least two amino acids and no limitation is placed on the maximum number of amino acids which may comprise a protein’s or peptide’s sequence. As used herein the term “amino acid” refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D and L optical isomers, amino acid analogs and peptidomimetics. As used herein, a consecutive amino acid sequence refers to a sequence having at least two amino acids. However, it is noted that a consecutive amino acid sequence of a first part and a second part does not limit the amino acid sequence to have the first part directly conjugated to the second part. It is also possible that the first part is linked to the second part via a third part, such as a link, thus forming one consecutive amino acid sequence. A polynucleotide disclosed herein can be delivered to a cell or tissue using a gene delivery vehicle. “Gene delivery,” “gene transfer” “mRNA-based delivery”, “transducing,” and the like as used herein, are terms referring to the introduction of an exogenous polynucleotide 31 4914-9544-4227.1 Atty Docket No.116639-2730 (sometimes referred to as a “transgene”) into a host cell, irrespective of the method used for the introduction. Such methods include a variety of well-known techniques such as vector-mediated gene transfer (by, e.g., viral infection / transfection, or various other protein-based or lipid-based gene delivery complexes, including for example protamine complexes, lipid nanoparticles, polymeric nanoparticles, lipid-polymer hybrid nanoparticles, and inorganic nanoparticles, or combinations thereof) as well as techniques facilitating the delivery of “naked” polynucleotides (such as electroporation, “gene gun” delivery and various other techniques used for the introduction of polynucleotides). The introduced polynucleotide can be unmodified or can comprise one or more modifications; for example, a modified mRNA may comprise ARCA capping; enzymatic polyadenylation to add a tail of 100-250 adenosine residues; and substitution of one or both of cytidine with 5-methylcytidine and / or uridine with pseudouridine. The introduced polynucleotide may be stably or transiently maintained in the host cell. Stable maintenance typically requires that the introduced polynucleotide either contains an origin of replication compatible with the host cell or integrates into a replicon of the host cell such as an extrachromosomal replicon (e.g., a plasmid) or a nuclear or mitochondrial chromosome. A number of vectors are known to be capable of mediating transfer of genes to mammalian cells, as is known in the art and described herein. A “plasmid” is an extra-chromosomal DNA molecule separate from the chromosomal DNA which is capable of replicating independently of the chromosomal DNA. In many cases, it is circular and double-stranded. Plasmids provide a mechanism for horizontal gene transfer within a population of microbes and typically provide a selective advantage under a given environmental state. Plasmids may carry genes that provide resistance to naturally occurring antibiotics in a competitive environmental niche, or alternatively the proteins produced may act as toxins under similar circumstances. “Plasmids” used in genetic engineering are called “plasmid vectors”. Many plasmids are commercially available for such uses. The gene to be replicated is inserted into copies of a plasmid containing genes that make cells resistant to particular antibiotics and a multiple cloning site (MCS, or polylinker), which is a short region containing several commonly used restriction sites allowing the easy insertion of DNA fragments at this location. Another major use of plasmids is to make large amounts of proteins. In this case, researchers grow 32 4914-9544-4227.1 Atty Docket No.116639-2730 bacteria containing a plasmid harboring the gene of interest. Just as the bacterium produces proteins to confer its antibiotic resistance, it can also be induced to produce large amounts of proteins from the inserted gene. A “viral vector” is defined as a recombinantly produced virus or viral particle that comprises a polynucleotide to be delivered into a host cell, either in vivo, ex vivo or in vitro. Examples of viral vectors include retroviral vectors, adenovirus vectors, adeno- associated virus vectors, herpes simplex virus vectors, alphavirus vectors and the like. As used herein, the term “animal” refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term “mammal” includes both human and non-human mammals. In one aspect, a “subject” or “patient” to whom the therapies such as for example a combination of anti-GPR25 therapy and immune checkpoint inhibitor is administered is preferably a mammal such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc.) or a primate (e.g., monkey or human). The subject or patient can be a human, such as an adult patient or a pediatric patient. An “effective amount” or “efficacious amount” refers to the amount of an agent, or combined amounts of two or more agents, that, when administered for the treatment of a mammal or other subject, is sufficient to effect such treatment for the disease. The “effective amount” will vary depending on the agent(s), the disease and its severity and the age, weight, etc., of the subject to be treated. As used herein, a biological sample, or a sample, can be obtained from a subject, cell line or cultured cell or tissue. Exemplary samples include, but are not limited to, cell sample, tissue sample, tumor biopsy, liquid samples such as blood and other liquid samples of biological origin (including, but not limited to, ocular fluids (aqueous and vitreous humor), peripheral blood, sera, plasma, ascites, urine, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, cerumen, breast milk, broncheoalveolar lavage fluid, semen, prostatic fluid, cowper’s fluid or pre-ejaculatory fluid, female ejaculate, sweat, tears, cyst fluid, pleural and peritoneal fluid, pericardial fluid, ascites, lymph, chyme, 33 4914-9544-4227.1 Atty Docket No.116639-2730 chyle, bile, interstitial fluid, menses, pus, sebum, vomit, vaginal secretions / flushing, synovial fluid, mucosal secretion, stool water, pancreatic juice, lavage fluids from sinus cavities, bronchopulmonary aspirates, blastocyl cavity fluid, or umbilical cord blood. In some instances, the sample is a diseased tissue biopsy. In certain embodiments, the terms “disease” “disorder” and “condition” are used interchangeably herein, referring to asthma, an autoimmune disorder, or fibrotic disorder, a status of being diagnosed with asthma, an autoimmune disorder, or fibrotic disorder, or a status of being suspected of having asthma, an autoimmune disorder, or fibrotic disorder. As used herein, the term “extracellular matrix” (ECM) is a three-dimensional network of extracellular macromolecules, such as collagen, enzymes, and glycoproteins, that provide structural and biochemical support to surrounding cells. As used herein, the term “detectable marker” refers to at least one marker capable of directly or indirectly, producing a detectable signal. A non-exhaustive list of this marker includes enzymes which produce a detectable signal, for example by colorimetry, fluorescence, luminescence, such as horseradish peroxidase, alkaline phosphatase, β-galactosidase, glucose-6 phosphate, dehydrogenase, chromophores such as fluorescent, luminescent dyes, groups with electron density detected by electron microscopy or by their electrical property such as conductivity, amperometry, voltammetry, impedance, detectable groups, for example whose molecules are of sufficient size to induce detectable modifications in their physical and / or chemical properties, such detection may be accomplished by optical methods such as diffraction, surface plasmon resonance, surface variation, the contact angle change or physical methods such as atomic force spectroscopy, tunnel effect, or radioactive molecules such as32P,35S ,89Zr or125I. As used herein, the term “purification marker” refers to at least one marker useful for purification or identification. A non-exhaustive list of this marker includes His, lacZ, GST, maltose-binding protein, NusA, BCCP, c-myc, CaM, FLAG, GFP, YFP, cherry, thioredoxin, poly(NANP), V5, Snap, HA, chitin-binding protein, Softag 1, Softag 3, Strep, or S-protein. Suitable direct or indirect fluorescence marker comprise FLAG, GFP, YFP, RFP, dTomato, 34 4914-9544-4227.1 Atty Docket No.116639-2730 cherry, Cy3, Cy 5, Cy 5.5, Cy 7, DNP, AMCA, Biotin, Digoxigenin, Tamra, Texas Red, rhodamine, Alexa fluors, FITC, TRITC or any other fluorescent dye or hapten. As used herein, “immunophenotyping” refers to the analysis of heterogeneous populations of cells for the purpose of identifying the presence and proportions of the various populations in the sample. Antibodies are used to identify cells by detecting specific antigens (termed markers) expressed by these cells. In an aspect, the cell samples are characterized by immunophenotyping using techniques such as flow cytometry. In alternative aspects, characterizations of the various cell types, (such as T cells, B cells and their subsets) present in a cell sample may be carried out using any suitable methodology such as reverse transcriptase polymerase chain reaction (RT-PCR) or immunocytochemistry (IHC). The phrase “first line” or “second line” or “third line” or “fourth line” or “fifth line” refers to the order of treatment received by a patient. First line therapy regimens are treatments given first, whereas second or third line therapy are given after the first line therapy or after the second line therapy, respectively. As used herein, the term “T cell,” refers to a type of lymphocyte that matures in the thymus. T cells play an important role in cell-mediated immunity and are distinguished from other lymphocytes, such as B cells, by the presence of a T-cell receptor on the cell surface. T- cells may either be isolated or obtained from a commercially available source. “T cell” includes all types of immune cells expressing CD3 including T-helper cells (CD4+ cells), cytotoxic T- cells (CD8+ cells), natural killer T-cells, T-regulatory cells (Treg), Tissue-resident memory T cells (TRM cells), stem T cells and gamma-delta T cells. A “cytotoxic cell” includes CD8+ T cells, natural-killer (NK) cells, and neutrophils, which cells are capable of mediating cytotoxicity responses. Non-limiting examples of commercially available T-cell lines include lines BCL2 (AAA) Jurkat (ATCC® CRL-2902™), BCL2 (S70A) Jurkat (ATCC® CRL-2900™), BCL2 (S87A) Jurkat (ATCC® CRL-2901™), BCL2 Jurkat (ATCC® CRL-2899™), Neo Jurkat (ATCC® CRL-2898™), TALL-104 cytotoxic human T cell line (ATCC # CRL-11386). Further examples include but are not limited to mature T-cell lines, e.g., such as Deglis, EBT-8, HPB- MLp-W, HUT 78, HUT 102, Karpas 384, Ki 225, My-La, Se-Ax, SKW-3, SMZ-1 and T34; and immature T- cell lines, e.g., ALL-SIL, Be13, CCRF-CEM, CML-T1, DND-41, DU.528, EU-9, 35 4914-9544-4227.1 Atty Docket No.116639-2730 HD-Mar, HPB-ALL, H-SB2, HT-1, JK-T1, Jurkat, Karpas 45, KE-37, KOPT-K1, K-T1, L- KAW, Loucy, MAT, MOLT-1, MOLT 3, MOLT-4, MOLT 13, MOLT-16, MT-1, MT-ALL, P12 / Ichikawa, Peer, PER0117, PER-255, PF-382, PFI-285, RPMI-8402, ST-4, SUP-T1 to T14, TALL-1, TALL-101, TALL-103 / 2, TALL-104, TALL-105, TALL-106, TALL-107, TALL-197, TK-6, TLBR-1, -2, -3, and -4, CCRF-HSB-2 (CCL-120.1), J.RT3-T3.5 (ATCC TIB-153), J45.01 (ATCC CRL-1990), J.CaM1.6 (ATCC CRL-2063), RS4;11 (ATCC CRL-1873), CCRF-CEM (ATCC CRM-CCL-119); and cutaneous T-cell lymphoma lines, e.g., HuT78 (ATCC CRM-TIB- 161), MJ[G11] (ATCC CRL-8294), HuT102 (ATCC TIB-162). Null leukemia cell lines, including but not limited to REH, NALL-1, KM-3, L92-221, are a another commercially available source of immune cells, as are cell lines derived from other leukemias and lymphomas, such as K562 erythroleukemia, THP-1 monocytic leukemia, U937 lymphoma, HEL erythroleukemia, HL60 leukemia, HMC-1 leukemia, KG-1 leukemia, U266 myeloma. Non- limiting exemplary sources for such commercially available cell lines include the American Type Culture Collection, or ATCC, (http: / / www.atcc.org / ) and the German Collection of Microorganisms and Cell Cultures (https: / / www.dsmz.de / ). Tissue-Resident Memory T Cells, or TRM cells, refer to a subset of long-lived memory T cells that occupy various tissues without recirculating. TRM cells reside in tissues that create barriers against the outside environment and thus provide defense against repeatedly incoming pathogens. TRMs also play a role in the protection against malignancies. Three cell surface markers that has been associated with TRM are CD69, CD49a, and CD103. Transforming Growth Factor Beta, or TGF- β, is a growth and differentiation factor encoded by 33 genes in mammals and comprises homo- and heterodimers. Tissue resident memory cell” or “TRM” cells refer to a subset of long-lived memory T cells that occupy epithelial and mucosal tissues. A “cytotoxic cell” intends a cell that is capable of killing other cells or microbes. Examples of cytotoxic cells include but are not limited to CD8+ T-cells, certain CD4+ T-cells, double-negative T-cells, gamma delta T-cells, natural-killer (NK) cells, NK T-cells, and neutrophils, which cells are capable of mediating cytotoxicity responses. 36 4914-9544-4227.1 Atty Docket No.116639-2730 As used herein, the term “CD4+ cytotoxic T-cells” refers to a population of T-cells that express CD4 on their surface and, generally, are ThPOK- (downregulated). These CD4+ cytotoxic T-cells can also be characterized by CD8αα expression, downregulation of Gata3, and upregulation of Runx3 and Tbet. Sequences for the mentioned transcription factors and surface proteins are provided at the following accession numbers: ThPOK (Uniprot: O15156 (human); Q64321 (mouse); also known as ZBTB7B), Gata3 (Uniprot: P23771 (human); P23772 (mouse); P23825 (chicken)), Runx3 (Uniprot: Q13761 (human); Q64131 (mouse); Q91ZK1 (rat)); Tbet (Uniprot: Q9UL17 (human); Q5PSB0 (mouse); E1UGZ0 (rainbow trout), also known as TBX21), CD4 (Uniprot: P01730 (human); P06332 (mouse); P33705 (dog)), and CD8α (Uniprot: P01732 (human); P01731 (mouse); P33706 (dog), CD8αα being a homodimer of this protein). It should be understood that these sequences are non-limiting and that detection of any of these transcription factors and / or surface proteins may employ or target suitable isoforms, fragments, and biological equivalents thereof; further homologous and / or orthologous sequences for relevant species can be found through the Uniprot database, www.uniprot.org. The term “CD4+ T-cells” refers to T-cells that express CD4 on their surface and, generally, are ThPOK+ (upregulated); these cells include naïve CD4+ T-cells, Th1 T-cells, Th17 T-cells, and T-regulatory cells. It is well understood that surface markers, e.g., CD8αα and CD4, can be identified by antibodies to the listed surface markers, i.e., an anti- CD8α antibody or an anti-CD4 antibody. When used in this context the prefix “anti-” and the descriptor “antibody” refer to an antibody, fragment, derivative, or biological equivalent thereof that recognizes or binds the recited protein, e.g., anti-CD4 antibody recognizes and binds CD4. As used herein, the term “CD8+ cytotoxic T-cell” refers to a cytotoxic T-cell and / or a precursor thereof which is CD8+ and expresses CD8αα on its surface. The CD8αα surface expression is an indicator that these CD8+ cytotoxic T-cells have high affinity to the antigen against which they were generated. As used herein, “CD8αα” refers to a homodimer of CD8α (also known as CD8a) that may be expressed on the surface of certain T-cells. Non-limiting exemplary amino acid sequences for CD8α can be found in the Uniprot database under accession numbers P01732 (human CD8α); P01731 (mouse CD8α); P33706 (dog CD8α); other homologs of the same may also be found in the Uniprot database, i.e., at www.uniprot.org. “CD8αβ” refers to a heterodimer of CD8α and CD8β (also known as CD8b) that is expressed on the surface of 37 4914-9544-4227.1 Atty Docket No.116639-2730 CD8+T-cells. Non-limiting exemplary amino acid sequences for CD8β can be found in the Uniprot database under accession numbers P10966 (human CD8β); P10300 (mouse CD8β); P79336 (cat CD8β); other homologs of the same may also be found in the Uniprot database, i.e., at www.uniprot.org. As used herein, “anti- CD8α” and “anti- CD8β” refer to antibodies or fragments, derivatives, or biological equivalents thereof that recognizes and bind to CD8α and CD8β, respectively. These may be recombinantly expressed, generated by exposing antibody producing cells to CD8α or CD8β, or other means known in the art, using for example, the proteins described herein. Further they can be purchased from commercial vendors, such as but not limited to Becton Dickinson. “Frequency” of cells expressing any one particular molecule, biomarker, or antigen refers to the likelihood of or ratio of cells expressing the molecule, biomarker, or antigen compared to a population of T cells at large. G Protein-Coupled Receptor 25 (“GPR25) is a protein encoding gene that encodes a member of the G-protein coupled receptor 1 family. G-protein coupled receptors are membrane proteins which activate signaling cascades as a response to extracellular stress. Among its related pathways are GPCR downstream signaling and Class A / 1 (Rhodopsin-like receptors). The protein sequence of GPR25 is publicly available at https: / / useast.ensembl.org / Homo_sapiens / Transcript / Sequence_Protein?db=core;g=ENSG00000 170128;r=1:200872981-200874178;t=ENST00000304244 (accessed October 17, 2023) is reproduced below. MAPTEPWSPSPGSAPWDYSGLDGLEELELCPAGDLPYGYVYIPALYLAAFAVGLLGNAF VVWLLAGRRGPRRLVDTFVLHLAAADLGFVLTLPLWAAAAALGGRWPFGDGLCKLSS FALAGTRCAGALLLAGMSVDRYLAVVKLLEARPLRTPRCALASCCGVWAVALLAGLPS LVYRGLQPLPGGQDSQCGEEPSHAFQGLSLLLLLLTFVLPLVVTLFCYCRISRRLRRPPH VGRARRNSLRIIFAIESTFVGSWLPFSALRAVFHLARLGALPLPCPLLLALRWGLTIATCL AFVNSCANPLIYLLLDRSFRARALDGACGRTGRLARRISSASSLSRDDSSVFRCRAQAAN TASASW The nucleic acid sequence encoding the GPR25 protein is publicly available https: / / www.ncbi.nlm.nih.gov / nuccore / NM_005298.4 (accessed October 17, 2023) reproduced below. 38 4914-9544-4227.1 Atty Docket No.116639-2730 1 agagctgctg ccgcctgcgc ccagggctgc actccgcgca ggcctcatag ccaggccatg 61 gcccccacag agccctggag ccccagcccg gggtcagcgc cctgggacta ctcggggttg 121 gacggcctgg aggagctgga gctgtgtccg gccggggacc tgccctacgg ctacgtctac 181 atccccgcgc tctacctggc ggccttcgcc gtgggcctgc tgggcaacgc ctttgtggtg 241 tggctgctgg ccgggcggcg gggcccgcgg cggctggtgg ataccttcgt gctgcacctg 301 gcggcagctg acctgggctt cgtgctcacg ctgccgctgt gggccgcggc ggcggcgcta 361 ggcggccgct ggccgttcgg cgatggcctc tgcaagctca gcagcttcgc gctggcgggc 421 acgcgctgcg cgggcgcgct gctgctggcg ggcatgagcg tggaccgcta cctggccgtg 481 gtgaagctgc tcgaggcgag gccactgcgc accccgcgct gcgcgctggc ctcgtgctgc 541 ggcgtctggg ccgtggcgct gctggccggc ctgccctccc tggtctaccg ggggttgcag 601 cccctgcctg ggggccagga cagccagtgc ggcgaggagc cctcccacgc cttccagggc 661 ctcagcttgc tgctgctgct gctgaccttc gtgctgcccc tggtcgtcac cctcttctgc 721 tactgccgca tctcgcgccg cctgcgacgg ccgccgcacg tgggtcgggc ccggaggaac 781 tcgctgcgca tcatcttcgc catcgagagc acgtttgtgg gctcctggct gcccttcagc 841 gccctgcggg ccgtcttcca cctggcgcgt ctgggggcgc tgccgctgcc gtgccccctg 901 ctgctggcgc tgcgctgggg cctcaccatt gccacctgcc tggccttcgt caacagctgc 961 gccaacccgc tcatctacct cctgctggac cgctcattcc gagcccgggc gctggacggg 1021 gcctgcgggc gcaccggccg cctggcgcga aggatcagct cagcctcctc gctctccagg 1081 gacgacagtt ccgtgttccg ttgccgggcc caggccgcga acactgcctc ggcctcctgg 1141 tagctgcccc gggccgctgg aggtgggcgg cagcggagca tcgagaggag gccagagg Below are the murine and human amino acid sequence of GPR25. The homology of these sequences is provided in FIG.7A. Mouse MQSTEPWSPSWGTLSWDYSGSGSLDQVELCPAWNLPYGHAIIPALYLAA FAVGLPGNAFVVWLLSRQRGPRRLVDTFVLHLAAADLGFVLTLPLWAAAEARGGLWP FGDGLCKVSSFALAVTRCAGALLLAGMSVDRYLAVGRPLSARPLRSARCVRAVCGAA WAAAFLAGLPALLYRGLQPSLDGVGSQCAEEPWEALQGVGLLLLLLTFALPLAVTLICY WRVSRRLPRVGRARSNSLRIIFTVESVFVGCWLPFGVLRSLFHLARLQALPLPCSLLLAL RWGLTVTTCLAFVNSSANPVIYLLLDRSFRARARFGLCARAGRQVRRISSASSLSRDDSS VFRGRSPKVNSASATW Human MAPTEPWSPSPGSAPWDYSGLDGLEELELCPAGDLPYGYVYIPALYLAAF AVGLLGNAFVVWLLAGRRGPRRLVDTFVLHLAAADLGFVLTLPLWAAAAALGGRWPF GDGLCKLSSFALAGTRCAGALLLAGMSVDRYLAVVKLLEARPLRTPRCALASCCGVW 39 4914-9544-4227.1 Atty Docket No.116639-2730 AVALLAGLPSLVYRGLQPLPGGQDSQCGEEPSHAFQGLSLLLLLLTFVLPLVVTLFCYCR ISRRLRRPPHVGRARRNSLRIIFAIESTFVGSWLPFSALRAVFHLARLGALPLPCPLLLALR WGLTIATCLAFVNSCANPLIYLLLDRSFRARALDGACGRTGRLARRISSASSLSRDDSSV FRCRAQAANTASASW In general, antagonistic antibodies and / or agents have the ability to bind and deactivate the target receptor in a way that mimics the activity of the ligand. The agent may include a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA. An antagonistic anti GPR25 antibody intends an antibody, antigen binding fragment, derivative or other modification as described herein that recognizes and binds the GPR25 protein. The antagonizing antibodies or agents described in the application may bind to GPR25 to decrease, eliminate, and / or otherwise modulate the activity of the GPR25 receptor and / or the GPR25 expressing cell. Such activities may include proliferation or inhibition of cell signaling activities of the cell upon which the GPR25 receptor is expressed. The antagonistic antibodies or agents of this disclosure target and specifically bind to GPR25. In some aspects, the antagonistic antibody or agents bind the receptor in a manner that mimics the binding of the physiological ligand resulting in antibody-mediated antagonism. In some aspects, treatment with an antagonistic anti-GPR25 antibodies significantly impedes the progression of asthma, an autoimmune disorder or fibrotic disorder, which may be mediated via inhibition of CD8+ T cells. Immunotherapies utilizing antagonistic antibodies or agents, especially those targeting trimeric receptors like 4-1BB or CD40, require antibody crosslinking via Fcg receptors expressed on APCs for efficient T cell activation. Depending on the Immunoglobulin (IgG) antibody subclass, they bind to and can thus get crosslinked by Fcg receptors with different affinities. (Li et al., 2011; Nimmerjahn et al., 2005; Claus et al., 2019) Thus, the antibody subclass and the availability, type and degree of expression of Fcg receptors on APCs are critical determinants of immunotherapy treatment efficacy. As used herein, the terms “antibody,” “antibodies” and “immunoglobulin” includes whole antibodies and any antigen binding fragment or a single chain thereof. Thus the term “antibody” includes any protein or peptide containing molecule that comprises at least a 40 4914-9544-4227.1 Atty Docket No.116639-2730 portion of an immunoglobulin molecule. The terms “antibody,” “antibodies” and “immunoglobulin” also include immunoglobulins of any isotype, fragments of antibodies which retain specific binding to antigen, including, but not limited to, Fab, Fab′, F(ab)2, Fv, scFv, dsFv, Fd fragments, dAb, VH, VL, VhH, and V-NAR domains; minibodies, diabodies, triabodies, tetrabodies and kappa bodies; multispecific antibody fragments formed from antibody fragments and one or more isolated. Examples of such include, but are not limited to a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, at least one portion of a binding protein, chimeric antibodies, humanized antibodies, single-chain antibodies, and fusion proteins comprising an antigen- binding portion of an antibody and a non-antibody protein. The variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with an antigen. The constant regions of the antibodies (Abs) may mediate the binding of the immunoglobulin to host tissues. The term “anti-” when used before a protein name, anti-GPR25 for example, refers to a monoclonal or polyclonal antibody that binds and / or has an affinity to a particular protein. The antibodies can be polyclonal, monoclonal, multispecific (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity. Antibodies can be isolated from any suitable biological source, e.g., murine, rat, sheep and canine. The term “antibody fragment” refers to a portion of an intact antibody and refers to the antigenic determining variable regions of an intact antibody. In some embodiments, the term “antibody fragment” refers to at least one portion of an intact antibody, or recombinant variants thereof, and refers to the antigen binding domain, e.g., an antigenic determining variable region of an intact antibody, that is sufficient to confer recognition and specific binding of the antibody fragment to a target, such as an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, Fv fragments, scFv antibody fragments, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, and multi- specific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other 41 4914-9544-4227.1 Atty Docket No.116639-2730 epitope binding fragments of an antibody. An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (Fn3)(see U.S. Pat. No.6,703,199, which describes fibronectin polypeptide minibodies). “Fab” means a monovalent antigen- binding fragment of an immunoglobulin that is composed of the light chain and part of the heavy chain. F(ab′)2 means a bivalent antigen-binding fragment of an immunoglobulin that contains both light chains and part of both heavy chains. As used herein, the term “Fv fragment” or “variable domain fragment” refers to a VH domain and a VL domain of an antibody specifically binding to an antigen, both domains forming together a Fv fragment. In some embodiment, Fv fragments means an antibody fragment comprising the VHand VLdomains of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the Fv fragment polypeptide further comprises a polypeptide linker between the VH and VL domains polypeptide that enables the scFv to form. The term “scFv” refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived. Unless specified, as used herein an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VHor may comprise VH-linker-VL. As used herein, the term “antibody heavy chain” refers to the larger of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. As used herein, the term “antibody light chain” refers to the smaller of the two types of polypeptide chains present in all antibody molecules in their naturally occurring 42 4914-9544-4227.1 Atty Docket No.116639-2730 conformations. Kappa (κ) and lambda (λ) light chains refer to the two major antibody light chain isotypes. As used herein, the term “synthetic antibody” means an antibody, which is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage. The term should also be construed to mean an antibody, which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art. As used herein, the term “antibody variant” includes synthetic and engineered forms of antibodies which are altered such that they are not naturally occurring, e.g., antibodies that comprise at least two heavy chain portions but not two complete heavy chains (such as, domain deleted antibodies or minibodies); multi-specific forms of antibodies (e.g., bi-specific, tri-specific, etc.) altered to bind to two or more different antigens or to different epitopes on a single antigen); heavy chain molecules joined to scFv molecules and the like. In addition, the term “antibody variant” includes multivalent forms of antibodies (e.g., trivalent, tetravalent, etc., antibodies that bind to three, four or more copies of the same antigen. As used herein, the term “antigen” or “Ag” is defined as a molecule that provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically-competent cells, or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. A skilled artisan will understand that any DNA, which comprises a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an “antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full-length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit a desired immune response. Moreover, the skilled artisan will understand 43 4914-9544-4227.1 Atty Docket No.116639-2730 that an antigen need not be encoded by a “gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a biological fluid. The term “bispecific antibody” refers to an antibody that can simultaneously bind to two different receptors, epitopes or antigens. The bispecific antibodies of the instant disclosure may target and bind antigens on the same cells or different cells. In some aspects, the bispecific antibodies bind to GPR25 and a second molecule on the T cell. GPR25 may be expressed on a T cell. In some aspects, the second molecule is expressed on the same T cell. In one aspect, the bispecific antibodies of the claimed disclosure increase target specificity for GPR25 expressing T cells, while limiting undesirable off-target activity. In some aspects, the bispecific bind and modulate the expression or activity of GPR25 in or on the T cell or the GPR25 expressing T cells. As used herein, “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous antibody population. Monoclonal antibodies are highly specific, as each monoclonal antibody is directed against a single determinant on the antigen. The antibodies may be detectably labeled, e.g., with a radioisotope, an enzyme which generates a detectable product, a fluorescent protein, and the like. The antibodies may be further conjugated to other moieties, such as members of specific binding pairs, e.g., biotin (member of biotin-avidin specific binding pair), and the like. The antibodies may also be bound to a solid support, including, but not limited to, polystyrene plates or beads, and the like. Monoclonal antibodies may be generated using hybridoma techniques or recombinant DNA methods known in the art. A hybridoma is a cell that is produced in the laboratory from the fusion of an antibody-producing lymphocyte and a non-antibody producing cancer cell, usually a myeloma or lymphoma. A hybridoma proliferates and produces a continuous sample of a specific monoclonal antibody. Alternative techniques for generating or selecting antibodies include in vitro exposure of lymphocytes to antigens of interest, and screening of antibody display libraries in cells, phage, or similar systems. The term “human antibody” as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. 44 4914-9544-4227.1 Atty Docket No.116639-2730 The human antibodies disclosed herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Thus, as used herein, the term “human antibody” refers to an antibody in which substantially every part of the protein (e.g., CDR, framework, CL, CHdomains (e.g., CH1, CH2, CH3), hinge, (VL, VH)) is substantially non-immunogenic in humans, with only minor sequence changes or variations. Similarly, antibodies designated primate (monkey, baboon, chimpanzee, etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, and the like) and other mammals designate such species, sub-genus, genus, sub-family, family specific antibodies. Further, chimeric antibodies include any combination of the above. Such changes or variations optionally retain or reduce the immunogenicity in humans or other species relative to non- modified antibodies. Thus, a human antibody is distinct from a chimeric or humanized antibody. It is pointed out that a human antibody can be produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and / or light chain) genes. Further, when a human antibody is a single chain antibody, it can comprise a linker peptide that is not found in native human antibodies. For example, an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are considered to be of human origin. As used herein, a human antibody is “derived from” a particular germline sequence if the antibody is obtained from a system using human immunoglobulin sequences, e.g., by immunizing a transgenic mouse carrying human immunoglobulin genes or by screening a human immunoglobulin gene library. A human antibody that is “derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequence of human germline immunoglobulins. A selected human antibody typically is at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline 45 4914-9544-4227.1 Atty Docket No.116639-2730 sequences). In certain cases, a human antibody may be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. Typically, a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene. In certain cases, the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene. A “human monoclonal antibody” refers to antibodies displaying a single binding specificity which have variable and constant regions derived from human germline immunoglobulin sequences. The term also intends recombinant human antibodies. Methods to making these antibodies are described herein. In one embodiment, an antibody as used herein may be a recombinant antibody. The term “recombinant human antibody”, as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. Methods to making these antibodies are described herein. 46 4914-9544-4227.1 Atty Docket No.116639-2730 As used herein, chimeric antibodies are antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from antibody variable and constant region genes belonging to different species. As used herein, the term “humanized antibody” or “humanized immunoglobulin” refers to a human / non-human chimeric antibody that contains a minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a variable region of the recipient are replaced by residues from a variable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and capacity. Humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. The humanized antibody can optionally also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin, a non-human antibody containing one or more amino acids in a framework region, a constant region or a CDR, that have been substituted with a correspondingly positioned amino acid from a human antibody. In general, humanized antibodies are expected to produce a reduced immune response in a human host, as compared to a non-humanized version of the same antibody. The humanized antibodies may have conservative amino acid substitutions which have substantially no effect on antigen binding or other antibody functions. Conservative substitutions groupings include: glycine-alanine, valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine- valine, serine-threonine and asparagine-glutamine. The antibodies of the present disclosure may bind to an antigen or molecule. The terms “polyclonal antibody” or “polyclonal antibody composition” as used herein refer to a preparation of antibodies that are derived from different B-cell lines. They are a mixture of immunoglobulin molecules secreted against a specific antigen, each recognizing a different epitope. As used herein, the term “antibody derivative”, comprises a full-length antibody or a fragment of an antibody, wherein one or more of the amino acids are chemically modified by alkylation, pegylation, acylation, ester formation or amide formation or the like, e.g., for 47 4914-9544-4227.1 Atty Docket No.116639-2730 linking the antibody to a second molecule. This includes, but is not limited to, pegylated antibodies, cysteine-pegylated antibodies, and variants thereof. Complementarity determining regions (CDRs) are part of the variable region of an antibody or a T cell receptor generated by B-cell s and T-cells respectively, wherein these molecules bind to their specific antigen (also called epitope). In certain embodiments, the terms “variable region” and “variable domain” are used interchangeably, referring to the polypeptide of a light or heavy chain of an antibody that varies greatly in its sequence of amino acid residues from one antibody to another, and that determines the conformation of the combining site which confers the specificity of the antibody for a particular antigen. In a further embodiment, the variable region is about 90 amino acids long to about 200 amino acids long, including but not limited to about 100 amino acids long, or alternatively about 110 amino acids long, or alternatively about 120 amino acids long, or alternatively about 130 amino acids long, or alternatively about 140 amino acids long, or alternatively about 150 amino acids long, or alternatively about 160 amino acids long, or alternatively about 170 amino acids long, or alternatively about 180 amino acids long, or alternatively about 190 amino acids long. In certain embodiments, a variable region of an amino acid sequence, as used herein, refers to that the first about 100 amino acids, or alternatively about 110 amino acids, or alternatively about 120 amino acids, or alternatively about 130 amino acids, or alternatively about 140 amino acids, or alternatively about 150 amino acids of the amino acid sequence (including or excluding a signal peptide if applicable) is the variable region. A set of CDRs constitutes a paratope also called an antigen-binding site, which is a part of an antibody that recognizes and binds to an antigen. There are three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively, optionally from the amino terminus to the carboxyl terminus, on the amino acid sequence of a variable region of an antigen receptor, such as a heavy chain or a light chain. As used herein, CDRn refers to a CDRn in an immunoglobulin chain or derived from an immunoglobulin chain, wherein the number n is selected from 1-3. In one embodiment, CDRLn refers to a CDRn in a light chain or derived from a light chain, wherein the number n is selected from 1-3; while CDRHn refers to a CDRn in a heavy chain or derived from a heavy chain, wherein the number n is selected from 1-3. In certain embodiments, framework region (FR) refers to the part of a variable region which is not a CDR. In certain 48 4914-9544-4227.1 Atty Docket No.116639-2730 embodiments, FRn refers to a FR in a heavy chain or a light chain or derived from a heavy chain or a light chain, and wherein the number n is selected from 1-4. In certain embodiments, a variable region comprises or consists essentially of, or yet further consists of the following (optionally following the order as provided, and further optionally from the amino terminus to the carboxyl terminus): FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Variable regions and / or CDRs of an antibody or a fragment thereof can be determined by one of skill in the art, for example, using publicly or commercially available tools. Non-limiting examples of such tools include, IgBlast (accessible at www.ncbi.nlm.nih.gov / igblast / ), Scaligner (available from drugdesigntech at www.scaligner.com / ), IMGT rules and / or tools (see, for example, www.imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition.html, also accessible at www.imgt.org / ), Chothia Canonical Assignment (accessible at www.bioinf.org.uk / abs / chothia.html), Antigen receptor Numbering And Receptor CalssificatiIon (ANARCI, accessible at opig.stats.ox.ac.uk / webapps / newsabdab / sabpred / anarci / ), the Kabat numbering method / scheme (e.g., Kabat, E.A., et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242,) or the Paratome web server (accessible at www.ofranlab.org / paratome / , see Vered Kunik, et al, Nucleic Acids Research, Volume 40, Issue W1, 1 July 2012, Pages W521–W524). In general, antagonistic antibodies have the ability to bind and activate the target receptor in a way that mimics the activity of the ligand. An antagonistic anti-GPR25 antibody (anti-GPR25 antibody) intends an antibody, antigen binding fragment, derivative or other modification as described herein that recognizes and binds the GPR25protein. The antagonizing antibodies described in the application may bind to GPR25to increase, enhance, upregulate, and / or otherwise modulate the activity of the GPR25receptor and / or the GPR25expressing cell. Such activities may include proliferation and cell signaling activities of the cell upon which the GPR25receptor is expressed. The antagonistic antibodies of this disclosure target and specifically bind to GPR25. In some aspects, the antagonistic antibody binds the receptor in a manner that mimics the binding of the physiological ligand resulting in antibody-mediated antagonism. In some aspects, treatment with an antagonistic anti-GPR25antibodies significantly impedes 49 4914-9544-4227.1 Atty Docket No.116639-2730 progression of asthma, an autoimmune disorder, or a fibrotic disorder. Immunotherapies utilizing antagonistic antibodies, especially those targeting trimeric receptors like 4-1BB or CD40, require antibody crosslinking via Fcg receptors expressed on APCs for efficient T cell activation. Depending on the Immunoglobulin (IgG) antibody subclass, they bind to and can thus get crosslinked by Fcg receptors with different affinities. (Li et al., 2011; Nimmerjahn et al., 2005; Claus et al., 2019) Thus, the antibody subclass and the availability, type and degree of expression of Fcg receptors on APCs are critical determinants of immunotherapy treatment efficacy. However, the antagonistic activity of antibodies targeting co-stimulatory receptors depends on a variety of factors and does not always require Fc cross-linking. Such factors include but are not limited to antibody affinity, Fc modifications like glycoengineering or point mutations, the antibody subclass and antigen expression. “Immune response” broadly refers to the antigen-specific responses of lymphocytes to foreign substances. The terms “immunogen” and “immunogenic” refer to molecules with the capacity to elicit an immune response. All immunogens are antigens, however, not all antigens are immunogenic. An immune response disclosed herein can be humoral (via antibody activity) or cell-mediated (via T cell activation). The response may occur in vivo or in vitro. The skilled artisan will understand that a variety of macromolecules, including proteins, nucleic acids, fatty acids, lipids, lipopolysaccharides and polysaccharides have the potential to be immunogenic. The skilled artisan will further understand that nucleic acids encoding a molecule capable of eliciting an immune response necessarily encode an immunogen. The artisan will further understand that immunogens are not limited to full-length molecules, but may include partial molecules. As used herein, the term “inducing an immune response in a subject” or “modulating an immune response” are terms well understood in the art and intends that an increase or decrease of at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 100-fold, at least about 500-fold, or at least about 1000-fold or more in an immune response (i.e. T cell or antibody response) to an antigen (or epitope) and can be detected or measured by various methods known in the art. For example, the frequency or activity of antigen-specific T cells can be measured by multiple methods, including, but not limited to, flow cytometry, RNA-sequencing or in vitro assays. 50 4914-9544-4227.1 Atty Docket No.116639-2730 As used herein, the term “modulating activity” refers to increasing or decreasing the activity of specific T cell populations associated with an immune response. Modulating of activity may be accomplished by the administration of agents, including antibodies, that target and bind to specific T cell receptors in order to activate the T cell population expressing that molecule. Modulation may occur when the T cells are engaged by costimulatory ligands, antagonistic antibodies or cytokines. In some aspects, modulating activity may include the administration of an agent that targets a molecule on a T cell. In some aspects, the molecule is GPR25and the agent is an antibody that targets GPR25, thus activating the GPR25expressing T cell. An “immunotherapy agent” means a type of treatment which modulates a patient’s own immune system to treat asthma, an autoimmune disorder, or fibrotic disorder, including but not limited to a physical intervene, a chemical substance, a biological molecule or particle, a cell, a tissue or organ, or any combinations thereof, modulating a patient's immune response against asthma, an autoimmune disorder, or fibrotic disorder. Non-limiting examples of immunotherapy agents include antibodies, immune regulators, checkpoint inhibitors, an antisense oligonucleotide (ASO), a RNA interference (RNAi), a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) system, a viral vector,, and a CAR therapy. Antisense oligonucleotides (ASOs) are oligonucleotides capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20–24 (normally 21) base pairs in length, similar to miRNA, and operating within the RNA interference (RNAi) pathway. It interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation. As used herein, immune checkpoint refers to a regulator and / or modulator of the immune system). Their interaction activates either inhibitory or activating immune signaling 51 4914-9544-4227.1 Atty Docket No.116639-2730 pathways. Thus a checkpoint may contain one of the two signals: an stimulatory immune checkpoint that stimulates an immune response, and an inhibitory immune checkpoint inhibiting an immune response. In some embodiments, the immune checkpoint is crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. As used herein, the term “recombinant host cell,” “recombinant cell,” “engineered host cell,” or “engineered cell,” means a cell into which a recombinant expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” or “cell” as used herein. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in total DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation and / or change. A host cell includes a cell transfected or infected in vivo or in vitro with a recombinant vector, an expression vector, or a nucleic acid encoding an antibody of the present disclosure. A host cell, which comprises a recombinant vector, expression vector, or a nucleic acid encoding an antibody disclosed herein, may also be referred to as a “recombinant host cell,” “engineered host cell,” or “engineered cell”. As used herein, the term “host cell” refers to a cell, which may be used in a process for purifying an immunogenic protein or recombinant antibody in accordance with the present disclosure. Such host cell expresses the protein of interest (the antibody disclosed herein). A host cell may also be referred to as a protein-expressing cell. “Host cell” refers not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. A host cell, according to the present disclosure, may be, but is not limited to, prokaryotic cells, eukaryotic cells, archeobacteria, bacterial cells, insect cells, yeast, mammal cells, and / or plant cells. Bacteria envisioned as host cells can be either gram-negative or gram- 52 4914-9544-4227.1 Atty Docket No.116639-2730 positive, e.g. Escherichia coli, Erwinia sp., Klebsellia sp., Lactobacillus sp. or Bacillus subtilis. In some embodiments, the host cell is a yeast cell. In that embodiment, the yeast host cell is selected from the group consisting of Saccharomyces cerevisiae, Hansenula polymorpha, and Pichia pastoris. A “composition” is intended to mean a combination of active agent and another compound or composition, inert (for example, a detectable agent or label) or active, such as an adjuvant , diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers. Carriers also include pharmaceutical excipients and additives proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri, tetra-oligosaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1- 99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid / antibody components, which can also function in a buffering capacity, include alanine, arginine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this technology, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol. A “pharmaceutical composition” is intended to include the combination of an active polypeptide, polynucleotide or antibody with a carrier, inert or active such as a solid support, making the composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. “Pharmaceutically acceptable carriers” refers to any diluents, excipients, or carriers that may be used in the compositions disclosed herein. Pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium 53 4914-9544-4227.1 Atty Docket No.116639-2730 sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. They may be selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. “Administration” can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents are known in the art. Route of administration can also be determined and method of determining the most effective route of administration are known to those of skill in the art and will vary with the composition used for treatment, the purpose of the treatment, the health condition or disease stage of the subject being treated, and target cell or tissue. Non-limiting examples of route of administration include oral administration, nasal administration, injection, and topical application. An agent of the present disclosure can be administered for therapy by any suitable route of administration. It will also be appreciated that the optimal route will vary with the condition and age of the recipient, and the disease being treated. The term “effective amount” refers to a quantity sufficient to achieve a desired effect. In the context of therapeutic or prophylactic applications, the effective amount will depend on the type and severity of the condition at issue and the characteristics of the individual subject, such as general health, age, sex, body weight, and tolerance to pharmaceutical compositions. With respect to immunogenic compositions, in some embodiments the effective 54 4914-9544-4227.1 Atty Docket No.116639-2730 amount will depend on the intended use, the degree of immunogenicity of a particular antigenic compound, and the health / responsiveness of the subject's immune system, in addition to the factors described above. The skilled artisan will be able to determine appropriate amounts depending on these and other factors. In the case of an in vitro application, in some embodiments the effective amount will depend on the size and nature of the application in question. It will also depend on the nature and sensitivity of the in vitro target and the methods in use. The skilled artisan will be able to determine the effective amount based on these and other considerations. The effective amount may comprise one or more administrations of a composition depending on the embodiment. “Simultaneous use” as used herein refers to the administration of the two compounds of the composition according to the disclosure in a single and identical pharmaceutical form or at the same time in two distinct pharmaceutical forms. “Separate use” as used herein refers to the administration, at the same time, of the two compounds of the composition according to the disclosure in distinct pharmaceutical forms. “Sequential use” as used herein refers to the successive administration of the two compounds of the composition according to the disclosure, each in a distinct pharmaceutical form. The term “tissue” is used herein to refer to tissue of a living or deceased organism or any tissue derived from or designed to mimic a living or deceased organism. The tissue may be healthy, diseased, and / or have genetic mutations. The biological tissue may include any single tissue (e.g., a collection of cells that may be interconnected) or a group of tissues making up an organ or part or region of the body of an organism. The tissue may comprise a homogeneous cellular material or it may be a composite structure such as that found in regions of the body including the thorax which for instance can include lung tissue, skeletal tissue, and / or muscle tissue. Exemplary tissues include, but are not limited to those derived from liver, lung, thyroid, skin, pancreas, blood vessels, bladder, kidneys, brain, biliary tree, duodenum, abdominal aorta, iliac vein, heart and intestines, including any combination thereof. 55 4914-9544-4227.1 Atty Docket No.116639-2730 As used herein, “treating” or “treatment of” a condition, disease or disorder or symptoms associated with a condition, disease or disorder refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of condition, disorder or disease, stabilization of the state of condition, disorder or disease, prevention of development of condition, disorder or disease, prevention of spread of condition, disorder or disease, delay or slowing of condition, disorder or disease progression, delay or slowing of condition, disorder or disease onset, amelioration or palliation of the condition, disorder or disease state, and remission, whether partial or total. “Treating” can also mean prolonging survival of a subject beyond that expected in the absence of treatment. “Treating” can also mean inhibiting the progression of the condition, disorder or disease, slowing the progression of the condition, disorder or disease temporarily, although in some instances, it involves halting the progression of the condition, disorder or disease permanently. Thus in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination. In certain non-limiting embodiments, the condition, disease, or disorder capable of being treated by the aspects disclosed herein is an autoimmune or fibrotic disorder, disease, or condition, proinflammatory condition, or an aberrant immune response. In certain embodiments, the autoimmune or fibrotic disorder, disease, or condition, proinflammatory condition, or an aberrant immune response is selected from the group consisting of polymyositis, vasculitis syndrome, giant cell arteritis, Takayasu arteritis, relapsing, polychondritis, acquired hemophilia A, Still’s disease, adult-onset Still’s disease, amyloid A amyloidosis, polymyalgia rheumatic, 56 4914-9544-4227.1 Atty Docket No.116639-2730 Spondyloarthritides, Pulmonary arterial hypertension, graft-versus-host disease, autoimmune myocarditis, contact hypersensitivity (contact dermatitis), gastro-esophageal reflux disease, erythroderma, Behcet’s disease, amyotrophic lateral sclerosis, transplantation, rheumatoid arthritis, juvenile rheumatoid arthritis, malignant rheumatoid arthritis, Drug-Resistant Rheumatoid Arthritis, Neuromyelitis optica, Kawasaki disease, polyarticular or systemic juvenile idiopathic arthritis, psoriasis, nonalcoholic fatty liver disease, primary biliary cholangitis, autoimmune hepatitis, autoimmune kidney disease, chronic obstructive pulmonary disease (COPD), Castleman’s disease, asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent),, allergic encephalomyelitis, arthritis, arthritis chronica progrediente, reactive arthritis, psoriatic arthritis, enterophathic arthritis, arthritis deformans, rheumatic diseases, spondyloarthropathies, ankylosing spondylitis, Reiter syndrome, hypersensitivity (including both airway hypersensitivity and dermal hypersensitivity), allergies, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, erythema nodosum leprosum, Sjögren’s Syndrome, inflammatory muscle disorders, polychondritis, Wegener’s granulomatosis, dermatomyositis, Steven-Johnson syndrome, chronic active hepatitis, myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn’s disease, Irritable Bowel Syndrome, endocrine ophthalmopathy, scleroderma, Grave’s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, vaginitis, proctitis, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, juvenile diabetes (diabetes mellitus type I), autoimmune haematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia (ITP), autoimmune uveitis, uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, glomerulonephritis (with and without nephrotic syndrome), idiopathic nephrotic syndrome or minimal change nephropathy, inflammatory disease of skin, cornea inflammation, myositis, loosening of bone implants, metabolic disorder, atherosclerosis, dislipidemia, bone loss, osteoarthritis, osteoporosis, periodontal disease of obstructive or inflammatory airways diseases, bronchitis, pneumoconiosis, pulmonary emphysema, acute and hyperacute inflammatory reactions, acute infections, septic shock, endotoxic shock, adult respiratory distress syndrome, meningitis, pneumonia, cachexia wasting syndrome, stroke, herpetic stromal keratitis, dry eye disease, iritis, conjunctivitis, keratoconjunctivitis, Guillain-Barre syndrome, Stiff-man syndrome, 57 4914-9544-4227.1 Atty Docket No.116639-2730 Hashimoto’s thyroiditis, autoimmune thyroiditis, encephalomyelitis, acute rheumatic fever, sympathetic ophthalmia, Goodpasture’s syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome, Addison’s disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, atopic dermatitis, eczematous dermatitis, aphthous ulcer, lichen planus, autoimmune alopecia, Vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, sensorineural hearing loss, idiopathic bilateral progressive sensorineural hearing loss, autoimmune polyglandular syndrome type I or type II, immune infertility and immune-mediated infertility. The term “prevent” refers to a decrease in the occurrence of a disease or disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment. In one aspect, the term “treatment” excludes “prevention.” In one embodiment, the term “disease” or “disorder” as used herein refers to allergy (optionally, a food allergy or an allergic reaction), hypersensitivity, asthma, inflammatory response or inflammation. In one embodiment, the term “disease” or “disorder” as used herein refers to a status of being diagnosed with allergy (optionally, a food allergy or an allergic reaction), hypersensitivity, asthma, inflammatory response or inflammation, a status of being suspect of having allergy (optionally, a food allergy or an allergic reaction), hypersensitivity, asthma, inflammatory response or inflammation, or a status of at high risk of having allergy (optionally, a food allergy or an allergic reaction), hypersensitivity, asthma, inflammatory response or inflammation. As used herein, a “symptom” of a disease includes any clinical or laboratory manifestation associated with the disease and is not limited to what a subject can feel or observe. The compositions used in accordance with the disclosure can be packaged in dosage unit form for ease of administration and uniformity of dosage. The term "unit dose" or "dosage" refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of the composition calculated to produce the desired responses in association with its administration, i.e., the appropriate route and regimen. The quantity to be administered, both according to number of treatments and unit dose, depends on the result and / or protection desired. Precise amounts of the composition also depend on the judgment of the 58 4914-9544-4227.1 Atty Docket No.116639-2730 practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the subject, route of administration, intended goal of treatment (alleviation of symptoms versus cure), and potency, stability, and toxicity of the particular composition. Upon formulation, solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described herein. As used herein, the term “specifically binds,” with respect to an antibody, means an antibody or binding fragment thereof (e.g., Fv fragment or scFv) which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species. But, such cross-species reactivity does not itself alter the classification of an antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, such cross reactivity does not itself alter the classification of an antibody as specific. In some instances, the terms “specific binding” or “specifically binding,” can be used in reference to the interaction of an antibody, a protein, a chimeric antigen receptor, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, a chimeric antigen receptor recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope “A,” the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled “A” and the antibody, will reduce the amount of labeled A bound to the antibody. In some embodiments, the Fv fragment further comprises a linker domain to generate a single chain variable fragment (scFv). In one embodiment, the linker domain is operably linked to the heavy chain variable domain and the light chain variable domain. In some embodiments, the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and the scFv retains the specificity of the intact antibody from which it is derived. In one embodiment, 59 4914-9544-4227.1 Atty Docket No.116639-2730 the flexible polypeptide linker includes, but are not limited to, (Gly4 Ser)4 or (Gly4 Ser)3. In another embodiment, the linker includes multiple repeats of (Gly2Ser), (GlySer) or (Gly3Ser). MODES FOR CARRYING OUT THE DISCLOSURE Compositions Disclosed herein are methods of treating one or more of asthma, an autoimmune disease, or a fibrotic disease in a subject, determining prognosis of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease, determining the responsiveness of a subject to one or more of asthma, an autoimmune disease, or a fibrotic disease therapies in a subject that modulates GPR25. Also disclosed herein are methods for screening for a GPR25 asthma, an autoimmune disease, or a fibrotic treatment in a subject. In some aspects, provided herein is a method of treating autoimmune disease, inflammatory disease, and / or aberrant immune responses, including asthma, or eliciting an anti- inflammatory response in a subject in need thereof. In yet another aspect, provided herein are methods of inhibiting the proliferation of TRM cells in a subject. In yet another aspect, provided herein are methods of inhibiting the development of stem-like TRM cells in a subject. In some aspects, the methods comprise, consist of, or consist essentially of modulating the expression of G Protein-Coupled Receptor 25 (GPR25) in the patient. In some aspects, the methods comprise, consist of, or consist essentially of administering to the subject an effective amount of an agent to inhibit the activity of a population of T-cells expressing GPR25, thereby treating the one or more of asthma, the autoimmune disease, or fibrotic disease in the subject. In yet another aspect, the methods comprise, consist of, or consist essentially of administering to the subject an effective amount of an agent that reduces expression of GPR25 in T-cells, thereby treating the one or more of asthma, the autoimmune disease, or the fibrotic disease in the subject. In some aspects, the T cells comprise, consist of, or consist essentially of CD4+ or CD8+ T-cells. In some aspects, the T cells comprise, consist of, or consist essentially of CD8+ T-cells. In some aspects, the T cells comprise, consist of, or consist essentially of tissue resident memory (TRM) cells. 60 4914-9544-4227.1 Atty Docket No.116639-2730 In some aspects, the agent comprises, consists of, or consists essentially of a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA. In some aspects, the siRNA or miRNA is complementary to at least a fragment of a polynucleotide encoding GPR25. In some aspects, administration of the agent induces lower than baseline expression of GPR25 in the T cells. In some aspects, higher than baseline expression is at least about a 2-fold increase in expression of the one or more genes relative to baseline expression and / or lower than baseline expression is at least about a 2-fold decrease in expression of the one or more genes relative to baseline expression. In some aspects, baseline expression comprises, consists of, or consists essentially of normalized mean gene expression. In some aspects, the methods further comprise, consist of, or consist essentially of, administering to the subject an additional therapy for the one or more of asthma, the autoimmune disease, or the fibrotic disease. In some aspects, the additional therapy comprises, consists of, or consists essentially of one or more of bronchodilators, corticosteroids, and / or monoclonal antibodies for the treatment of one or more of asthma, the autoimmune, or the fibrotic disease. In yet another aspect, provided herein is a method of diagnosing one or more of asthma, an autoimmune disease, or a fibrotic disease in a subject, comprising, consisting of, or consisting essentially of contacting a sample isolated from the subject with an agent that detects the presence of GPR25 in the sample isolated from the subject, wherein the presence of the one or more genes at higher than baseline expression levels is a diagnostic indicator of asthma or the autoimmune or the fibrotic disease or wherein the absence of the one or more genes at higher or lower than baseline expression levels is not diagnostic indicator of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In some aspects, the sample comprises, consists of, or consists essentially of a TRM cell. In yet another aspect, provided herein is a method of diagnosing one or more of asthma, an autoimmune disease, or a fibrotic disease in a subject comprising, consisting of, or consisting essentially of contacting tissue-resident memory cells (TRMs) isolated from the subject or a sample isolated from the subject, with an antibody or agent that recognizes and binds 61 4914-9544-4227.1 Atty Docket No.116639-2730 to GPR25 to determine the frequency of TRMs expressing these proteins, wherein a high frequency of TRMs expressing these proteins is diagnostic of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of determining the density of tissue-resident memory cells (TRMs) in a sample isolated from a subject comprising, consisting of, or consisting essentially of measuring expression of GPR25 genes in the sample, wherein higher than baseline expression of the GPR25 indicates higher density of TRMs in the sample. In yet another aspect, provided herein is a method of determining prognosis of a subject having a one or more of asthma, an autoimmune disease, or a fibrotic disease comprising, consisting of, or consisting essentially of measuring the density of tissue-resident memory cells (TRM) in a sample isolated from the subject, wherein a low density of TRM indicates a more positive prognosis or wherein a high density of TRM indicates a more negative prognosis, optionally wherein the more negative prognosis comprises a decreased probability in the reduction of symptoms of asthma, the autoimmune, or the fibrotic disease and a lack of low density TRM indicates a more positive prognosis. In some aspects, increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of determining prognosis of a subject suffering from one or more of asthma, an autoimmune disease, or a fibrotic disease comprising, consisting of, or consisting essentially of contacting tissue-resident memory cells (TRMs) isolated from the subject with one or more of: an antibody or agent that recognizes and a protein encoded by a GPR25 gene, wherein a low density of TRMs indicates a more positive prognosis or wherein a high density of TRMs indicates a more negative prognosis. In some aspects, the more negative prognosis comprises a decreased probability in the reduction of symptoms of asthma, the autoimmune or the fibrotic disease, and wherein the more positive prognosis comprises an increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of determining prognosis of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease comprising, 62 4914-9544-4227.1 Atty Docket No.116639-2730 consisting of, or consisting essentially of contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds a protein encoded by a GPR25 gene to determine the frequency of TRMs expressing these proteins, wherein a low density of TRMs indicates a more positive prognosis or wherein a high density of TRMs indicates a more negative prognosis. In some aspects, the more negative prognosis comprises a decreased probability in the reduction of symptoms of the autoimmune or fibrotic disease, and wherein the more positive prognosis comprises an increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of determining prognosis of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease comprising contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds CD103 to determine the frequency of CD103+ TRMs or an antibody that recognizes and binds a protein encoded by a GPR25 gene to determine the frequency of TRMs expressing the protein, wherein a low density of TRMs indicates a more positive prognosis or wherein a high density of TRMs indicates a more negative prognosis, optionally wherein the more negative prognosis comprises a decreased probability in the reduction of symptoms of asthma, the autoimmune disease, or the fibrotic disease, and wherein the more positive prognosis comprises an increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of determining the responsiveness of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease to immunotherapy comprising, consisting of, or consisting essentially of contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds a protein encoded by a GPR25 gene to determine the frequency of TRMs in the subject, wherein a high frequency of TRMs indicates lack of responsiveness to immunotherapy. In yet another aspect, provided herein is a method of determining the responsiveness of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease to immunotherapy comprising, consisting of, or consisting essentially of contacting 63 4914-9544-4227.1 Atty Docket No.116639-2730 tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds a protein encoded by a GPR25 gene and, to determine the frequency of TRMs expressing these proteins, wherein a low frequency of TRMs expressing these proteins indicates responsiveness to immunotherapy. In yet another aspect, provided herein is a method of determining prognosis of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease comprising, consisting of, or consisting essentially of measuring the density of CD103 or a protein encoded by a GPR25 gene in a sample isolated from the subject, wherein a low density of TRM indicates a more positive prognosis or wherein a high density or TRM indicates a more negative prognosis. In some another, the more negative prognosis comprises, consists of, or consists essentially a decreased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In some aspects the lack of low density TRM indicates a more positive prognosis. In some aspects, the more negative prognosis comprises, consists of, or consists essentially of the increased probability reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease. In yet another aspect, provided herein is a method of identifying a subject that will or is likely to respond to one or more of an asthma therapy, an autoimmune therapy, or a fibrotic disease therapy, comprising, consisting of, or consisting essentially of contacting a sample isolated from the subject with an agent that detects the presence of GPR25 in the sample, wherein the presence of the one or more genes at higher or lower than baseline expression levels indicates that the subject is likely to respond to the one or more of the asthma therapy, the autoimmune therapy, or the fibrotic disease therapy. In some aspects, baseline expression comprises, consists of, or consists essentially of normalized mean gene expression. In some aspects, higher than baseline expression of the one or more genes is at least about a 2-fold increase in expression relative to baseline expression and / or lower than baseline expression of the one or more genes is at least about a 2-fold decrease in expression relative to baseline expression. In some aspects, the methods further comprise, consist of, or consist essentially of administering to a patient in need thereof an asthma therapy, an autoimmune therapy, or a 64 4914-9544-4227.1 Atty Docket No.116639-2730 fibrotic disease therapy to the subject. In some aspects, the asthma therapy, the autoimmune therapy, or the fibrotic disease therapy comprises, consists of, or consists essentially of one or more of hormonal therapy, immunotherapy, bronchodilators, corticosteroids, or monoclonal antibodies. In some aspects, the sample is contacted with an agent. In some aspects, the agent comprises, consists of, or consists essentially of a detectable lab or tag. In some aspects, the detectable label or tag comprises, consists of, or consists essentially of a radioisotope, a metal, horseradish peroxidase, alkaline phosphatase, avidin or biotin. In yet another aspect, the agent comprises, consists of, or consists essentially of comprises a polypeptide that binds to an expression product encoded by the gene, or a polynucleotide that hybridizes to a nucleic acid sequence encoding all or a portion of the gene. In some aspects, the antibody comprises, consists of, or consists essentially of an IgG, IgA, IgM, IgE or IgD, or a subclass thereof. In some aspects, the IgG comprises, consists of, or consists essentially of IgG1, IgG2, IgG3 or IgG4. In some aspects, the antigen binding fragment comprises, consists of, or consists essentially of a Fab, Fab’, F(ab’)2, Fv, Fd, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv) or VL or VH. In some aspects, the agent is contacted with the sample in conditions favoring binding of the agent to GPR25. In some aspects of the methods disclosed herein, the agent is contacted with the sample in conditions favoring binding of the agent to GPR25. In some aspects, the methods comprise, consist of, or consist essentially of detection by immunohistochemistry (IHC), in-situ hybridization (ISH), ELISA, immunoprecipitation, immunofluorescence, chemiluminescence, radioactivity, X-ray, nucleic acid hybridization, protein-protein interaction, immunoprecipitation, flow cytometry, Western blotting, polymerase chain reaction, DNA transcription, Northern blotting and / or Southern blotting. In some aspects, the sample comprises, consists of, or consists essentially of cells, tissue, an organ biopsy, an epithelial tissue, a lung, respiratory or airway tissue or organ, a circulatory tissue or organ, a skin tissue, bone tissue, muscle tissue, head, neck, brain, skin, bone and / or blood sample. 65 4914-9544-4227.1 Atty Docket No.116639-2730 In some aspects, the one or more of the asthma or autoimmune disease, or fibrotic disease comprises, consists of, or consists essentially of polymyositis, vasculitis syndrome, giant cell arteritis, Takayasu arteritis, relapsing, polychondritis, acquired hemophilia A, Still's disease, adult-onset Still's disease, amyloid A amyloidosis, polymyalgia rheumatic, Spondyloarthritides, Pulmonary arterial hypertension, graft-versus-host disease, autoimmune myocarditis, contact hypersensitivity (contact dermatitis), gastro-esophageal reflux disease, erythroderma, Behcet's disease, amyotrophic lateral sclerosis, transplantation, rheumatoid arthritis, juvenile rheumatoid arthritis, malignant rheumatoid arthritis, Drug-Resistant Rheumatoid Arthritis, Neuromyelitis optica, Kawasaki disease, polyarticular or systemic juvenile idiopathic arthritis, psoriasis, nonalcoholic fatty liver disease, primary biliary cholangitis, autoimmune hepatitis, autoimmune kidney disease, chronic obstructive pulmonary disease (COPD), Castleman’s disease, asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic encephalomyelitis, arthritis, arthritis chronica progrediente, reactive arthritis, psoriatic arthritis, enterophathic arthritis, arthritis deformans, rheumatic diseases, spondyloarthropathies, ankylosing spondylitis, Reiter syndrome, hypersensitivity (including both airway hypersensitivity and dermal hypersensitivity), allergies, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, erythema nodosum leprosum, Sjögren’s Syndrome, inflammatory muscle disorders, polychondritis, Wegener's granulomatosis, dermatomyositis, Steven-Johnson syndrome, chronic active hepatitis, myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, Irritable Bowel Syndrome, endocrine ophthalmopathy, scleroderma, Grave’s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, vaginitis, proctitis, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, juvenile diabetes (diabetes mellitus type I), autoimmune haematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia (ITP), autoimmune uveitis, uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, glomerulonephritis (with and without nephrotic syndrome), idiopathic nephrotic syndrome or minimal change nephropathy, inflammatory disease of skin, cornea inflammation, myositis, loosening of bone implants, metabolic disorder, atherosclerosis, dislipidemia, bone loss, osteoarthritis, osteoporosis, periodontal disease of obstructive or inflammatory airways diseases, 66 4914-9544-4227.1 Atty Docket No.116639-2730 bronchitis, pneumoconiosis, pulmonary emphysema, acute and hyperacute inflammatory reactions, acute infections, septic shock, endotoxic shock, adult respiratory distress syndrome, meningitis, pneumonia, cachexia wasting syndrome, stroke, herpetic stromal keratitis, dry eye disease, iritis, conjunctivitis, keratoconjunctivitis, Guillain-Barre syndrome, Stiff-man syndrome, Hashimoto's thyroiditis, autoimmune thyroiditis, encephalomyelitis, acute rheumatic fever, sympathetic ophthalmia, Goodpasture’s syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome, Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, atopic dermatitis, eczematous dermatitis, aphthous ulcer, lichen planus, autoimmune alopecia, Vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, sensorineural hearing loss, idiopathic bilateral progressive sensorineural hearing loss, autoimmune polyglandular syndrome type I or type II, immune infertility and immune-mediated infertility. Kits Finally, provided herein is a kit comprising, or consisting essentially of, or yet further consisting of one or more of the isolated T-cells and / or the composition of this disclosure and instructions for use. In one particular aspect, the present disclosure provides kits for performing the methods of this disclosure as well as instructions for carrying out the methods of the present disclosure. The kits are useful for diagnosing asthma, or an autoimmune disease, or a fibrotic disease in a subject from a biological sample taken from the subject e.g., any bodily fluid including, but not limited to, e.g., sputum, serum, plasma, lymph, cystic fluid, urine, stool, cerebrospinal fluid, acitic fluid or blood and including biopsy samples of body tissue. The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed. Methods for preparing protein extracts or membrane extracts of cells are known in the art and can be readily adapted in order to obtain a sample which is compatible with the system utilized. The kit components, (e.g., reagents) can be packaged in a suitable container. The kit can also comprise, or alternatively consist essentially of, or yet further consist of, e.g., a buffering agent, a preservative or a protein-stabilizing agent. The kit can further comprise, or 67 4914-9544-4227.1 Atty Docket No.116639-2730 alternatively consist essentially of, or yet further consist of components necessary for detecting the detectable-label, e.g., an enzyme or a substrate. The kit can also contain a control sample or a series of control samples, which can be assayed and compared to the test sample. Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the assays performed using the kit. The kits of the present disclosure may contain a written product on or in the kit container. The written product describes how to use the reagents contained in the kit. As amenable, these suggested kit components may be packaged in a manner customary for use by those of skill in the art. For example, these suggested kit components may be provided in solution or as a liquid dispersion or the like. EXPERIMENTAL EXAMPLES Example 1: Introduction Immunological memory is a hallmark of adaptive immunity and the basis of vaccination7. Tissue-resident memory CD8+T (TRM) cells are a distinct population of memory T cells that primarily reside within tissues and respond immediately against pathogens invading barrier tissues, thus representing the first-line of defense1,2. TRM cells are phenotypically, functionally, transcriptionally, and metabolically distinct from circulating memory T cell subsets8-12like central memory T (TCM) and effector memory T (TEM) cells. For example, TRM cells lack expression of molecules required for tissue egress and trafficking to lymph nodes like S1PR1, S1PR5, C-C motif chemokine receptor (CCR)7 and CD62L2,13, and mostly express high levels of CD69, CD49a, and C-X-C motif chemokine receptor (CXCR)6, which play important roles in the tissue retention and localization of TRM cells14-16. The majority of TRM cells that reside within the epithelium also express the ⍺E integrin, CD1038,17, whereas, TRM cells that reside in non-epithelial tissues, such as liver10,15and kidney18,19do not express high levels of CD10310,15,20,21, presumably reflecting the lack of tight junctions in the sinusoidal endothelium. Although the molecules that play an important role in the development and function of TRMcells are not fully understood, several studies have defined the key transcriptional regulators such as Hobit, Blimp-1, Runx3, Etv5, Id3, fatty acid binding proteins 68 4914-9544-4227.1 Atty Docket No.116639-2730 (FABPs)10,20-23, and cytokines such as interleukin (IL)-15 and transforming growth factor beta (TGF-β) that contribute to TRM cell development and maintenance4,24-26. Besides their protective role in infections, it is now well-appreciated that TRM cells also play a critical role in cancer immunosurveillance27,28. Several studies have shown a positive association between tumor TRMcells and favorable clinical outcome in patients with breast cancer29,30, cervical cancer31, esophageal cancer32, gastric cancer33, liver cancer34, head and neck cancer35, lung cancer36, melanoma37, and pancreatic cancer38. These results suggest that the abundance of TRMcells in the tumor tissue is a prognostic indicator for survival outcomes. Functional studies in murine tumor models have further confirmed the pivotal role of TRMcells in driving anti-tumor immune responses22,23. Thus, targets that modulate the magnitude and quality of TRM responses are likely to have a potential therapeutic role in certain infections and cancer types as well as in autoimmune diseases, where TRMcells play a pathogenic role39. Unbiased gene expression studies in humans and mice have discovered a number of gene transcripts that are highly enriched for their expression in TRMcells isolated from various tissues and tumor types10,20,22,23,25,30,35,36,40. However, the functional role of the molecules encoded by TRM-enriched gene transcripts is not well-defined. One such molecule is a poorly characterized G protein-coupled receptor (GPR), called GPR2541. GPRs are the largest superfamily of transmembrane receptors in the genome42, they interact with a large number of extracellular ligands43and transmit intracellular signals by activating heterotrimeric guanine nucleotide-binding proteins44. The structure and cellular localization of GPRs make them attractive targets for drug development45. Applicant’s recent transcriptomic study showed that GPR25 is expressed at significantly higher levels in TRM cells compared with non-TRM cells in the human lung and tumor tissues36. GPR25 has long been considered an orphan receptor with no known endogenous ligand. However, a recent study reported that C-X-C motif chemokine 17 (CXCL17), a chemokine expressed mainly by epithelial cells in the respiratory tract and non- intestinal mucosae tissue, functions as a ligand for GPR25 and mediates lymphocyte homing to these tissues46. Additionally, Gpr25 also has been reported to have a ligand-independent constitutive activity47. In this study, using genetic models, Applicant demonstrate that Gpr25 plays an important role in the development and function of TRM cells in the liver and lung. 69 4914-9544-4227.1 Atty Docket No.116639-2730 Tissue-resident memory (TRM) CD8+T cells are key players that orchestrate protective anti-viral and anti-tumor immune responses1-3. The molecules that support their development and function are not fully defined. Here, Applicant report on the regulation and function of a G-protein coupled receptor, GPR25 that is expressed at high levels in TRM cells compared to non-TRMcells. TGF-β, a key cytokine involved in the development of TRMcells4, induces the expression of GPR25 in CD8+T cells, and SMAD1, a key transcription factor downstream of TGF-β signaling5, binds to TRM-associated cis-regulatory elements in the GPR25 locus. Adoptively transferred T cells from Gpr25-deficient mice showed no significant differences in their accumulation in the liver and lung of recipient mice after viral infection, but they exhibited impaired development into TRM cells. In a tumor challenge model, Gpr25- deficient memory T cells showed significantly reduced expansion and a diminished capacity to control lung metastasis compared to Gpr25-sufficient T cells. Single-cell transcriptomic analysis indicated that Gpr25 deficiency impacted the development of TRMcells with stem-like transcriptional features, including expression of TCF1, a key transcription factor promoting stemness in T cells6. Notably, following antigen re-challenge, Gpr25-deficient TRMcells displayed defects in their ability to differentiate into secondary TRM cells and maintain the TRM cell population. Gpr25-deficient T cells showed negative enrichment for TGF-β signature genes and impaired responses to TGF-β, indicating that Gpr25 enhances TGF-β signaling to promote the development of TRMcells. Applicant’s findings support the concept that modulating Gpr25 function may be an attractive therapeutic option to boost the magnitude and quality of TRM responses generated in the context of infection and cancer. Example 2: GPR25 Antagonism in Tissue resident memory T Cells TGF-β induces expression of GPR25 in CD8+T cells Applicant previously found that GPR25 expression was significantly increased in both lung and tumor-infiltrating CD8+TRM cells when compared to non-TRM cells36. Notably, the expression of GPR25 was strongly correlated with the expression of several key TRM-associated genes, such as ZNF683, RBPJ, ITGAE, ITGA1, S1PR1 and S1PR536. Because TGF-β is known to tightly regulate the expression of many TRM-associated genes4, Applicant tested its role in regulating the expression of GPR25. TGF-β treatment resulted in rapid induction of GPR25 in 70 4914-9544-4227.1 Atty Docket No.116639-2730 primary human CD8+T cells that were polyclonally activated in vitro by using anti-CD3 and ant- CD28 antibodies (FIG.1A). To determine how TGF-β signaling regulates expression of GPR25, Applicant analyzed assay for transposase-accessible chromatin using sequencing (ATAC-seq) profile of the GPR25 locus in human CD8+T cell subsets36,48. Three regions (C1, C2, C3) upstream of GPR25 transcription start site (TSS) displayed prominent transposase accessible peaks (ATAC-seq peaks) in tumor-infiltrating CD8+TRM cells compared to cell types not expressing GPR25 like non-TRMcells or circulating naïve CD8+T cells (FIG.1B, top panel). The C2 region, however, displayed prominent transposase accessibility in activated CD8+T cells. Applicant’s analysis suggested that these three cis-regulatory regions are likely to be involved in the regulation of GPR25 with C1,2,3 regions associated with TRMcells and C2 region with T cell receptor (TCR) activation. Notably, analysis of ENCODE transcription factor ChIP-seq data49showed that C1, C2 and C3 cis-regulatory regions bind to nuclear factor of activated T-cells (NFAT) and Suppressor of Mothers Against Decapentaplegic (SMAD)1, key transcription factors downstream of TCR50and TGF-β signaling5, respectively, suggesting that expression of GPR25 is likely to be co-regulated by these signaling pathways (FIG.1B, bottom panel). Applicant next assessed suitability of mouse models for testing the role of GPR25 in the development of TRM cells in vivo. First, Applicant noted that GPR25 is highly conserved across species with 75% sequence homology with the murine ortholog (FIG.7A). Second, similar to the observation in human T cells, Gpr25 expression was readily induced by TGF-β in murine CD8+T cells that were activated in vitro by cross-linking TCR and CD28, but its expression gradually declined over time (FIG.1C). Third, in unmanipulated wildtype C57BL / 6 mice (> 90 days old), CD8+T cells in a non-lymphoid organs such as small intestinal intra- epithelial lymphocytes (siIEL) and liver, especially those expressing the TRM marker CD6910,15,20, expressed higher levels of Gpr25 transcripts when compared to splenic CD8+T cells, which comprise mainly of circulating naïve and central memory T cells (TCMcells) (FIG. 1D and FIG.7B). Thus, in both mice and humans, GPR25 is a TGF-β inducible gene that is selectively expressed in TRM cells. 71 4914-9544-4227.1 Atty Docket No.116639-2730 Gpr25 promotes development of liver TRMcells. To investigate the role of Gpr25 in the development of TRM cells, Applicant utilized the well-established mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV)-Armstrong-OVA that is reported to induce CD8+TRM cells in multiple tissues, such as liver, kidney and intestine, as well as circulating CD8+effector memory (TEM) and central memory (TCM) T cells in the lymphoid tissues9,10,17,22. By breeding CD45.1.2 Gpr25+ / +(Gpr25 wild-type, WT) mice and CD45.2 Gpr25- / -(Gpr25 knock out, KO) mice with OT-I TCR transgenic mice, which express the transgenic T cell receptor (TCR) specific to SIINFEKL peptide of ovalbumin (OVA)51, Applicant generated mice with congenically marked Gpr25- sufficient (Gpr25+ / +) and Gpr25-deficient (Gpr25- / -) OT-I CD8+T cells (see Methods). Importantly, adoptive transfer of these congenically distinct OT-I T cells into CD45.1 recipient mice before infection with LCMV-OVA intraperitoneally (i.p.) allowed us to track the development of antigen (OVA)-specific memory T cell subsets in various tissues52. In this model, Applicant first confirmed that TRM cells (CD45.1.2+CD62L−CD69+T cells in the liver) generated from the adoptively transferred OT-I CD8+T cells expressed higher levels of Gpr25 transcripts when compared to OT-I TCMand TEMcells (CD45.1.2+CD62L+CD69- and CD45.1.2+CD62L−CD69−T cells in the spleen, respectively) (FIGS.8A – 8C). Consistent with their tissue-resident properties, TRMcells expressed significantly lower levels of transcripts encoding for sphigosine-1-phosphate receptor (S1PR1), which promotes egress of T cells from tissue compartments53(FIG.8C, right panel). To assess the relative role of Gpr25 in the development in TRM cells, Applicant co-transferred equal numbers of congenically distinct Gpr25+ / +OT-I (WT) and Gpr25- / -OT-I (KO) CD8+T cells into CD45.1 recipient mice before infection with LCMV-OVA (i.p.) and then 90 days post-infection (dpi) compared the frequencies and memory phenotypes of transferred T cells in the spleen, liver and small intestine intraepithelial lymphocyte compartment (siIEL) (FIG.2A and FIG.8D). Applicant found relatively equal proportions of Gpr25+ / +and Gpr25- / -OT-I T cells in the spleen, liver and siIEL (FIG.2B), which suggested that the Gpr25 deficiency did not influence the accumulation of T cells in these tissue compartments. Further, Gpr25 deficiency also did not impact the memory phenotypes of transferred T cells in the spleen (FIG. 8E), a tissue compartment that is largely devoid of TRMcells. However, in the liver, the 72 4914-9544-4227.1 Atty Docket No.116639-2730 frequency of Gpr25- / -TRM cells, marked by CD69 expression, was significantly reduced when compared to Gpr25+ / +TRMcells, indicating a potential defect in the development of TRMcells (mean 27% versus 17%; FIG.8E). The liver TRM cells (CD69+), as expected, co-expressed CXCR615,20, but lacked expression of CD103 (FIG.2C), a TRMmarker for cells localized in the epithelial compartment10,15,20, and KLRG1 (FIG.8E), a marker of effector memory T cells54, as reported previously15,20. Another notable finding was that the frequency of TRMcells in the siIEL compartment was not significantly different between Gpr25+ / +and Gpr25- / -OT-I T cells (FIG. 2C and FIG.8E), which suggested that Gpr25 is dispensable for the development of TRM cells in the siIEL compartment. Applicant next performed parabiosis experiments to assess the residency potential of Gpr25+ / +and Gpr25- / -liver TRMcells. TRMcells were generated in vivo by transferring equal numbers of congenically distinct Gpr25+ / +OT-I (WT) and Gpr25- / -OT-I (KO) T cells into CD45.1 recipient mice (host) before infection with LCMV-OVA. To specifically assess the residency potential of TRM cells generated in this model, circulatory OT-I cells were first depleted by administrating anti-Gr-1 antibody2530 days post infection and then host mice were conjoined with naïve CD8KO mice (parabiont recipient) that lack CD8+T cells (FIG.2D). Thirty days post-parabiosis, Gpr25+ / +and Gpr25- / -OT-I T cells accumulated in equal proportions in the host liver (FIG.2E). However, in the spleen of CD8KO parabiont recipient mice, Applicant observed a significantly higher proportion of Gpr25- / -OT-I (CD45.2) cells to Gpr25+ / +OT-I (CD45.1.2) cells (FIG.2E). This finding suggested that Gpr25-deficient TRM cells had lesser tissue-resident potential i.e., were able to enter the circulation of parabiont recipient mice, when compared to Gpr25-sufficient TRMcells. Together, these results demonstrate that Gpr25 supported the development of liver TRMcells. Gpr25 deficiency impairs early stages of TRMcell development Studies have shown that the first wave of effector T cells entering tissue compartments can bear features of TRM cells54, and over time, in response to tissue-derived signals like TGF-β, these cells develop into established TRMcells. To assess if Gpr25 is impacting the early stages of TRM cell development, Applicant compared the phenotype of adoptively co-transferred Gpr25+ / +and Gpr25- / -OT-I CD8+T cells in the liver at earlier time 73 4914-9544-4227.1 Atty Docket No.116639-2730 points following LCMV-OVA infection (FIG.3A). In the first 48 hours after infection, Applicant found no differences in the frequency, activation and proliferation status of transferred Gpr25+ / +versus Gpr25- / -OT-I T cells in the liver (FIG.3B and FIGS.9A – 9C). Even 5 days post infection, Gpr25 deficiency had no measurable impact on either the frequency or phenotype (KLRG1+effectors) of transferred OT-I cells in the liver (FIG.3C). Also at day 5, very few transferred OT-I T cells co-expressed the liver TRM markers CD69 and CXCR6; however, by day 12, Applicant could see a distinct population of CD69+CXCR6+OT-I T cells specifically in the liver but not spleen, which indicated that this population represented potential TRM precursor cells (FIGS.3C – 3E). Notably, Gpr25 deficiency resulted in a reduction of the frequency of these cells and a corresponding increase in KLRG1+effectors cells (FIG.3C). Applicant found relatively equal proportions of Gpr25+ / +and Gpr25- / -OT-I T cells in the liver on days 5, 12, and 30 post infection (FIG.3D), suggesting that Gpr25 has no impact on the accumulation and development of memory OT-I cells. By day 30, when the infection is cleared and memory responses are well-established55,56, the effects of Gpr25 on the formation of TRMcells (CD69+CXCR6+cells) and effector memory T cells (CD69−KLRG1+cells) were maintained (FIG.3E). These CD69+T cells expressed the memory marker CD44, were IL7R+KLRG1−, markers of memory precursor cells56, and lacked expression of the TCMmarker CD62L, confirming that this population represented bona fide TRM cells (FIG.9D). Together, these results suggested that Gpr25 supports the differentiation of TRM cells over effector memory T cells even during the early stages of memory T cell development. Gpr25 supports the generation of stem-like TRM cells Applicant next asked if TRM cells that develop from Gpr25-deficient OT-I T cells exhibit qualitative differences when compared to those that develop from Gpr25-sufficient OT-I T cells. Differential gene expression analysis revealed marked differences in transcriptional profiles between Gpr25+ / +and Gpr25- / -TRM cells isolated from the liver of recipient mice 30 days post LCMV infection (FIG.3A, FIG.4A, FIG.10A and Table 1). Applicant found that Gpr25+ / +TRM cells displayed significant positive enrichment of gene signatures linked to stem- like T cells compared to Gpr25- / -TRMcells (FIG.4B and Table 3), while also displaying negative enrichment for gene signatures linked to effector cells. Notably, Gpr25+ / +TRMcells expressed lower levels of transcripts encoding for cytotoxicity-related effector cell molecules 74 4914-9544-4227.1 Atty Docket No.116639-2730 like granzyme B, granzyme K and perforin, and higher levels of transcripts encoding for transcription factors like T cell factor 1 (Tcf1, encoded by Tcf7) and lymphoid enhancer-binding factor 1 (Lef1) (FIG.10A), which have been shown to play important roles in the initiation and maintenance of stem-like and self-renewal potential of memory T cells as well as restraining their effector differentiation57-59. Applicant confirmed by real-time quantitative polymerase chain reaction (qPCR) and intracellular staining that TCF1 encoding transcripts and TCF1 protein levels are higher in Gpr25+ / +compared to Gpr25- / -liver TRMcells (FIG.4C, FIG.4D). Interestingly, as early as 12 days post LCMV infection, transferred Gpr25+ / +OT-1 T cells in the liver of recipient mice were significantly enriched for stem-like T cell gene signatures (FIG.10B and Table 3), indicating that Gpr25 is likely to promote a stem-like program in the early stages of memory T cell development. Because Gpr25- / -TRMcells display defects in the generation of stem-like TCF1- expressing cells, Applicant hypothesized that following secondary infection, Gpr25- / -TRM cells are likely to show defects in the generation of secondary TRMcell population i.e., maintenance of TRM pool following re-infection. Given the capacity of adoptively transferred TRM cells, including liver TRMcells, to migrate and form secondary TRMcells at the same tissue of origin after re-infection15,23,60,61, Applicant utilized this secondary transfer approach to test whether Gpr25 deficiency impacted the generation of secondary TRMcells in the liver. To this end, Applicant performed secondary co-transfer of congenically distinct Gpr25+ / +and Gpr25- / -liver TRMcells, generated as described in the LCMV-OVA-induced TRMmodel (FIG.3A), into CD45.1 naïve recipient mice before infection with LCMV-OVA (i.p.) (FIG.4E). Thirty days after infection, Applicant found relatively equal numbers of transferred Gpr25+ / +and Gpr25- / -OT-I T cells in the liver (FIG.4F), indicating no major defects in the ability of Gpr25-deficient TRM cells to migrate and generate memory T cells in the liver. However, the frequency of Gpr25- deficient TRMcells that differentiate into secondary TRMcells (CD69+CXCR6+) in the liver was significantly reduced when compared to Gpr25-sufficient TRM cells (FIG.4G), while the frequency of secondary TEMcells (KLRG1+CD62L−CD69−) was increased (FIG.4H and FIG. 10C). These results indicate that Gpr25-deficient TRM cells display defects in their ability to differentiate into secondary TRMcells following antigen re-challenge. Thus, by supporting the generation of TCF1-expressing TRMcells with stem-like features, Gpr25 is likely to play an 75 4914-9544-4227.1 Atty Docket No.116639-2730 important role not only in the development of primary TRM cells but also in the generation of secondary TRM cell population in the liver. Gpr25 enhances T cell responses to TGF-β To assess how Gpr25 may influence the generation of stem-like TRM cells, Applicant focused on TGF-β signaling, which it is known to play an important role both in the generation of TRMcells62-67and the maintenance of TCF1-dependent stem-like program in CD8+memory T cells68. Notably, Applicant found a significant positive enrichment of TGF-β signature genes in Gpr25+ / +TRMcells compared to Gpr25- / -TRMcells in the liver of recipient mice (FIG. 4I). This pattern was evident in Gpr25+ / +T cells even during the early stages of infection (FIG. 10D; day 12 post infection). Thus, Applicant’s analysis of the transcriptomes of TRMcells suggested that Gpr25 may influence their responsiveness to TGF-β. To test this hypothesis, Applicant stimulated primary CD8+T cells in vitro with TGF-β for 24 hours and examined the phosphorylation status of SMAD proteins, which are the canonical transcriptions down-stream of TGF-β signaling69-71. As expected, Applicant found significantly lower expression levels of phosphorylated SMAD2 and SMAD3 proteins (pSMAD2 / SMAD3) in Gpr25- / -CD8+T cells compared to Gpr25+ / +cells (FIG.4J). In addition, Applicant found that CD8+T cells overexpressing Gpr25 showed higher levels of pSMAD2 / SMAD3 when compared to T cells expressing the empty vector (FIG.4K). Together, these finding supported the hypothesis that Gpr25 likely amplifies TGF-β signaling to influence the development of stem-like TRM cells. Gpr25 promotes development of lung TRMcells Given that GPR25 expression was selectively higher in human lung TRM cells compared to non-TRMcells36, Applicant utilized the LCMV-OVA infection model to ask if Gpr25 played an important role in the generation of lung TRM cells (FIG.11A). Applicant found equal proportions of adoptively transferred Gpr25+ / +and Gpr25- / -OT-I T cells in the lungs at day 30 and day 120 following infection with LMCV-OVA delivered intra-peritoneally (FIG.11B). However, unlike the findings in small intestine intraepithelial lymphocytes (siIELs) (FIG.2A), only a very small fraction of transferred OT-I cells co-expressed the canonical lung TRMmarkers CD69 and CD103 (FIG.11C). Therefore, to induce the generation of a larger pool of CD69+CD103+lung TRM cells, Applicant utilized the intratracheal (i.t.) route for both co- 76 4914-9544-4227.1 Atty Docket No.116639-2730 transferring OT-I T cells (Gpr25+ / +and Gpr25- / -) and infecting the naïve CD45.1 recipient mice with LCMV-OVA22,72-74(FIG.5A). Relatively equal proportions of Gpr25+ / +and Gpr25- / -OT-I T cells were seen in the lungs (FIG.5B). Thirty days after infection, Applicant were able to detect a distinct population of CD69+CD103+OT-I TRM cells in the lungs (FIG.5C). Notably, the ability of Gpr25-deficient OT-I T cells to develop into CD69+CD103+TRMcells in the lungs was significantly reduced when compared to Gpr25-sufficient OT-I T cells (FIG.5C and FIG. 11D). To gain further insights into the mechanisms that may explain how Gpr25 promotes the development of CD69+CD103+TRMcells in the lungs, Applicant performed single- cell transcriptome analysis of Gpr25+ / +and Gpr25- / -OT-I memory T cells that were isolated from lung tissue 30 days after LCMV-OVA infection (i.t.) (see Methods and FIG.7). Based on transcriptomic features, OT-I T cells clustered into two major subsets; notably, a greater fraction of Gpr25+ / +versus Gpr25- / -OT-I memory T cells (62% versus 38%) were observed in cluster 0 (FIG.5D). Similar to Applicant’s findings in liver TRM cells (FIG.4A, FIG.4B), compared to cluster 1, cluster 0 cells, which were enriched for Gpr25+ / +T cells, expressed lower levels of transcripts encoding for molecules linked to effector properties like perforin, granzyme B, granzyme A, and higher levels of transcripts encoding for molecules linked to stem-like properties such as TCF1 and IL7R (FIG.5E, FIG.5F, and FIG.11E), This finding suggested that, similar to Applicant’s findings in the liver tissue, Gpr25 is likely to promoted the development stem-like TCF-1-expressing T cells as opposed to effector T cells. To validate this finding, Applicant adoptively transferred Gpr25+ / +and Gpr25- / -OT-I T cells into separate cohorts of CD8KO recipient mice and then infected them with LCMV-OVA (i.t.) (FIG.5G). As expected, Applicant found that the frequency of TCF1-expressing CD8+T cells in the lungs were significantly lesser in transferred Gpr25- / -OT-I T cells compared to Gpr25+ / +OT-I T cells (FIG. 5H). Applicant’s transcriptomic analysis also showed that T cells in cluster 0, which were enriched for Gpr25+ / +T cells when compared to cluster 1, displayed lower expression of transcripts encoding for the transcription factors ZEB2 and S1PR5, a sphingone-1-phosphate receptor that promotes egress of cells from tissues75(FIG.5E and FIG.5F). A recent study reported that the robust generation of TRM cells required TGF-β induced down-regulation of the 77 4914-9544-4227.1 Atty Docket No.116639-2730 transcription factor ZEB2 and its target gene S1PR513, which in turn promoted the sequestration of cells in the tissues. Taken together, it is tempting to speculate that Gpr25 may also play a role in the downregulation of ZEB2-S1PR5 axis, potentially by modulating TGF-β signaling and thus favoring the generation of TRMcells in the lungs. Gpr25-deficient T cells fail to control lung metastasis. To determine if Gpr25-deficient OT-I memory T cells in the lungs display any functional impairment, Applicant examined their capacity to control the growth of lung metastases in a model of secondary challenge with OVA-expressing B16F10 melanoma (B16F10-OVA) cells. Applicant first verified that transferred OT-I memory T cells (OT-1 transfer), generated as previously described in FIG.5A, provide better control of lung metastasis when compared to endogenous anti-tumor responses in mice that did not receive OT-I cells (no OT-1 transfer group) (FIG.12A, FIG.12B). In addition, to minimize the contribution of circulating T cells to the control of metastasis, Applicant administered FTY720, a sphingosine-1- phosphate receptor antagonist that blocks egress of cells from lymph nodes76, thus allowing us to primarily assess the functional role of T cells resident in the lungs (FIG.12A). Mice that received FTY720 treatment developed more metastatic nodulus compared to mice that that did not receive FTY720 treatments, highlighting the relative contribution of circulating T cells to control of lung metastasis (FIG.12B). More importantly, mice that received FTY720 treatment developed lesser number of metastatic nodules compared to cohorts of mice that did not receive OT-1 T cells, which suggested that lung memory T cells per se can provide control of metastasis independent of replenishment from circulating T cells (FIG.12B, FIG.12C). To assess if Gpr25-deficient memory T cells display impaired secondary lung T cell responses in the tumor challenge model, Applicant co-transferred equal numbers of congenically distinct Gpr25+ / +and Gpr25- / -OT-I CD8+T cells prior to i.t. infection with LCMV- OVA, waited for 30 days to allow for the generation of memory OT-I T cells in the lungs as described in FIG.5A, and then challenged the recipient mice with B16F10-OVA tumor cells i.v. to induce metastasis (FIG.6A). Thirteen days after tumor inoculation, Applicant found that the frequency of Gpr25-sufficient OT-I cells in the lungs was significantly higher when compared to Gpr25-deficient OT-I cells (FIG.6B), indicating a competitive advantage for Gpr25-sufficient 78 4914-9544-4227.1 Atty Docket No.116639-2730 OT-I memory T cells to expand following secondary antigen (OVA) challenge with OVA- expressing tumor cells that metastasize to the lungs. Based on this finding, Applicant hypothesized that Gpr25-sufficient OT-I memory T cells are likely to possess greater capacity to control lung metastasis. To test this hypothesis, two independent cohorts of CD45.1 wildtype (FIG.6C) recipient mice received either Gpr25+ / +OT-I or Gpr25- / -OT-I CD8+T cells prior to i.t. infection with LCMV-OVA, then 30 days after infection, mice were challenged i.v. with B16F10-OVA cells and assessed for degree of lung metastasis following FTY720 treatment. Applicant found that the number of metastatic nodules was significantly lower in mice that received Gpr25- sufficient OT-I T cells when compared to those that received Gpr25-deficient OT-I cells (FIG. 6D). To exclude the contribution of host CD8+T cells, Applicant utilized CD8KO mice as recipients and tested the effects of Gpr25+ / +OT-I or Gpr25- / -OT-I CD8+T cells in controlling lung metastasis (FIG.6E). As controls, cohorts of CD8KO mice that did not receive T cells were also included to specifically assess the contribution of transferred OT-I T cells on outcomes. As expected, Applicant found that CD8KO mice receiving Gpr25-deficient OT-I cells had poor survival outcomes, with nearly 50% death rate, while most CD8KO mice receiving Gpr25- sufficient OT-I cells survived at the time of analysis (FIG.6F). Additionally, the number of metastatic nodules was significantly lower in CD8KO mice that received Gpr25-sufficient OT-I T cells when compared to those that received Gpr25-deficient OT-I cells or had no transfer of OT-1 T cells (FIG.6G). Overall, Applicant’s results suggest that Gpr25 is likely to have an important T cell-intrinsic role in the control of anti-tumor immune responses in a lung metastasis model. In Applicant’s previous transcriptomic survey36, GPR25 emerged as one of the top differentially expressed genes in the lung and tumor-infiltrating CD8+TRM cells when compared to non-TRMcells. In this study, Applicant show that GPR25 expression is induced in CD8+T cells by TGF-β signaling. Because three TRM-associated cis-regulatory regions in the GPR25 locus can bind to SMAD1, the key transcription factor downstream of TGF-β signaling, Applicant propose that GPR25 is likely to be a direct target gene of TGF-β. In an LCMV infection model, Applicant demonstrate that Gpr25 plays a key role in supporting the development of TCF1-expressing stem-like TRMcells in liver and lungs but not those that 79 4914-9544-4227.1 Atty Docket No.116639-2730 develop in the siIEL compartment. Future studies using other tissue-specific models of TRM generation can be utilized to examine the role of Gpr25 in tissue compartments like the skin, colon, upper airways and female reproductive tract. By using a lung metastasis model, Applicant highlight the T cell-intrinsic role of Gpr25 in anti-tumor immunity by supporting TRMresponses. Given the importance of TRM cells in anti-tumor immune responses, Applicant reasons that approaches to modulate TRM responses by targeting the activity of GPR25 may hold promise in relevant clinical settings. Applicant’s single-cell transcriptomic analysis of Gpr25-sufficient and Gpr25- deficient memory T cells provided several mechanistic insights. Notably, Gpr25-sufficient TRM cells were enriched for molecules that promote a stem-like memory program, whereas Gpr25- deficient TRM cells were enriched for molecules linked to an effector program. These results provide an interesting insight, suggesting potential heterogeneity within TRM cell population with some TRMcells exhibiting more stem-like features, including expression of TCF1, that may contribute to the maintenance of the TRMcell pool and enabling rapid re-expansion upon antigen re-challenge. Applicant’s results suggest that Gpr25 supports the generation of TCF1-expressing TRM cells, i.e., a stem-like differentiation program while limiting the effector differentiation of TRMcells by augmenting TGF-β signaling68. Furthermore, Applicant’s analysis revealed that Gpr25-deficient memory T cells also displayed defects in downregulating the ZEB2-S1PR5 axis that is required for preventing T cell egress from tissues. This finding suggested that Gpr25 signaling is likely to enhance tissue retention of TRMcells, a notion that is supported by Applicant’s parabiosis studies. Based on recently published data that TGF-β signaling is essential for the maintenance of both the TCF1-dependent stem-like program in CD8+memory T cells68as well as for the down-regulation of ZEB2-S1PR5 axis to promote tissue retention13, Applicant’s findings suggest that Gpr25 mediates its effects on TRMdevelopment and maintenance by either directly or indirectly modulating TGF-β signaling. Finally, although GPR25 has been shown to have constitutive activity without ligand engagement41,47, identification of the endogenous ligand is likely to shed light on endogenous signals that modulate GPR25 activity in T cells. A recent study identified a chemoattractant chemokine CXCL17 as the ligand for GPR25, and reported that CXCL17- GPR25 functions as a chemoaffinity axis that mediates lymphocytes homing to lung, non- 80 4914-9544-4227.1 Atty Docket No.116639-2730 intestinal mucosa and CNS46. Applicant’s study highlights that Gpr25 has important non- chemotactic functions and supports the generation and maintenance of TRM cells in the liver and lung. Further functional studies under physiological conditions and employing genetic knock-out models (Gpr25-deficient mice) are likely to clarify the relative contribution of the chemotactic versus non-chemotactic function of Gpr25 in mediating protective immunity in infections and cancer. Discussion Applicant’s single-cell transcriptomic analysis of Gpr25-sufficient and Gpr25- deficient memory T cells provided several mechanistic insights. Notably, Gpr25-sufficient TRM cells were enriched for molecules that promote a stem-like memory program, whereas Gpr25- deficient TRM cells were enriched for molecules linked to effector program, which suggests that Gpr25 is likely to support a stem-like differentiation program whilst restraining the effector differentiation of TRMcells. Gpr25-deficient memory T cells also displayed defects in downregulating the ZEB2-S1PR5 axis that is required for preventing egress of T cells from the tissues, suggesting that Gpr25 signaling is likely to enhance tissue retention of TRM cells. Based on recently published data that TGF-β signaling is essential for the maintenance of both Tcf-1- dependent stem-like program in CD8+memory T cells as well as for the down-regulation of ZEB2-S1PR5 axis to promote tissue retention9, Applicant hypothesize that Gpr25 may mediate its effects on TRM development by either directly or indirectly modulating TGF-β signaling, which should be tested in future studies. Finally, although GPR25 is an orphan receptor and has been shown to have a constitutive activity without ligand engagement38,43, identification of the endogenous ligand is likely to shed light on endogenous signals that modulate GPR25 activity in T cells. Two potential ligands, Apelin and Apela, are known to activate GPR25 and decrease intracellular cAMP levels in non-mammalian vertebrates66, however, their function in human T cells is not known. Future studies to identify physiological ligand(s) that selectively modulate GPR25 signaling in humans and mice are likely to facilitate the development of therapies that target the GPR25 signaling pathway for controlling TRMresponses in health and disease. 81 4914-9544-4227.1 Atty Docket No.116639-2730 Methods Mice. Gpr25 germline deletion mice (Gpr25- / -; RRID:MMRRC_047952-UCD) were generated by the Knock out Mouse Project (KOMP) and obtained from Mutant Mouse Resource and Resource Centers (MMRRC). Briefly, CRISPR guide(s) targeting of Gpr25 exon and Cas9 protein were microinjected or electroporated into C57BL / 6N zygotes to generate the Gpr25em2(IMPC)Bayallele (Gpr25- / -) and progeny were screened for the desired mutation. Gpr25- / -mice were viable, and were crossed with OT-I mice51, which express the transgenic TCR recognizing the OVA-specific class 1 epitope OVA257-264, to generate mice with Gpr25-deficient OT-I cells. OT-I mice (stock no.003831), CD45.2 C57BL / 6J mice (stock no.000664), CD45.1 mice (B6.SJL-PrprcaPepcb / BoyJ, stock no.002014) and CD8aKO mice (B6.129S2- Cd8atm1Mak / J, stock no.002665) were obtained from The Jackson Laboratory. Mice were maintained in specific-pathogen-free conditions in accordance with the Institutional Animal Care and Use Committees (IACUC) of the La Jolla institute for Immunology (LJI). All mice were maintained on a C57BL / 6 background and under a standard 12-hour light / 12-hour dark cycle. Mice were fed standard rodent chow and water ad libitum. Age- (8-12 weeks old) and sex- matched mice (female and male) were used in all experiments. All procedures were approved by the La Jolla Institute for Immunology Animal Ethics Committee. Infection model and adoptive T cell transfer. Lymphocytic choriomeningitis virus Armstrong strain (LCMV) expressing OVA (LCMV-OVA) was a gift from Ananda Goldrath (University of California, San Diego, CA) and generated by Juan-Carlos de la Torre (The Scripps Research Institute, La Jolla, CA)77. For co-transfer experiments, congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were mixed in a 1:1 ratio and 1 x 106total cells were adoptively co-transferred intravenously into CD45.1 recipient mice. Mice were then infected with 2 x 105plaque-forming units (PFU) of LCMV- OVA by intraperitoneal (i.p.) and memory T cell responses analyzed at indicated time points. For the secondary TRM generation model, congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRMcells, generated in the liver 30 days after the LCMV-OVA infection model (CD69+CD62L−OT-I CD8+T cells), were isolated from liver and adoptively transferred at a 1:1 ratio (5 x 103total cells) into CD45.1 naïve recipient mice before infection with 2 x 105PFU LCMV-OVA (i.p.). To enhance generation of TRM cells in lung tissue, congenically distinct 82 4914-9544-4227.1 Atty Docket No.116639-2730 Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were mixed in a 1:1 ratio and 1 x 106total cells were adoptively co-transferred intratracheally into CD45.1 recipient mice before infection with 5 x 104PFU of LCMV-OVA delivered intratracheally. Parabiosis Surgery. Mice were matched with body weight and body size, and co- housed for 2 weeks before experiments. For the surgery, mice were anesthetized with isoflurane, and flank hair was removed. Skin incision of approximately 0.5 cm was made above the elbow to 0.5 cm below the knee join in both animals. Mice were joined at the knees and elbows with 3.0 silk suture, connecting chest and inguinal adipose tissue with 6.0 PGA absorbable suture. Then the skin was joined with continuous sutures with 3.0 nylon suture. Parabiotic pairs were analyzed 30 days after surgeries. Mouse tissue processing and cell isolation. Liver tissue samples were cut into small pieces, passed through 70 µM cell strainers (Miltenyi Biotec) twice, and then resuspended at room temperature (RT) in red blood cell (RBC) lysis buffer (Cat. No.420301, BioLegend) for 3-5 min depending on cell number before further analysis. Spleens were processed into single- cell suspensions and resuspended in RBC lysis buffer to remove erythrocytes. Total CD8+T cells were isolated from spleen and liver single-cell suspensions to > 95% purity using a CD8+T cell negative selection kit (Stem Cell Technologies). For isolation of CD8+T cells from small intestinal epithelium, Peyer’s patches were first removed, and the intestinal tissue was cut longitudinally and washed of luminal contents. The tissue was then cut into 1-cm pieces and incubated in 25 ml of Hank’s balanced salt solution (HBSS) containing 25 mM HEPES, 1 mM DTT and 5mM EDTA in a shaker at 200 rpm for 20 min at 37˚C. Cells in the supernatant were collected and passed through a 40 / 80% Percoll density gradient to enrich for intraepithelial lymphocytes (siIEL). To isolate lymphocytes from lung tissues, lungs were well perfused with phosphate-buffered saline (PBS) and then cut into small pieces and dispersed for 15 min with 1 ml of digestion buffer (RPMI-1640 + 10% FBS, supplemented with 200 U / ml Type 2 Collagenase (Worthington) and 15 µg / ml DNase (Sigma)) while shaking at 37˚C. Flow cytometry. Single-cell suspensions were prepared and surface stained in fluorescence-activated cell sorting (FACS) buffer (PBS + 1.5% fetal bovine serum) for 20 minutes at 4˚C with the following antibodies (purchased from BioLegend): anti-CD8⍺ (53-6.7, 83 4914-9544-4227.1 Atty Docket No.116639-2730 Cat. No.100747); anti-CD8β (YTS156.7.7, Cat. No.126613); anti-CD45.1 (A20, Cat. No. 110730); anti-CD45.2 (104, Cat. No.109822); anti-CD69 (H1.2F3, Cat. No.104506); anti- CD103 (2E7, Cat. No.121422); anti-CXCR6 (SA051D1, Cat. No.151111); anti-KLRG1 (2F1 / KLRG1, Cat. No.138414); anti-CD62L (MEL-14, Cat. No.104408); anti-CD44 (IM7, Cat. No.103059); anti-CD127 (A7R34, Cat. No.135012); anti-PD-1 (29F.1A12, Cat. No.135220). For intracellular staining, cells were fixed and permeabilized with the “Foxp3 staining buffer set” (Cat. No.00-5523, eBioscience), following the manufacturer’s protocol, and then stained with anti-granzyme B (QA16A02, Cat. No.372208, BioLegend). For phosphorylated protein staining, cells were fixed by “BD Phosflow Lyse / Fix buffer” (558049, BD) at 37˚C in the dark for 10 minutes. Then the cells were permeabilized with 90% methanol at 4˚C for 30 minutes, and then stained with anti-Smad2(pS465 / pS467) / Smad39pS423 / pS425) (562586, BD). For flow cytometric analysis samples were acquired on LSRFortessa (BD Biosciences) or a LSRII flow cytometer (BD Biosciences) and then analyzed using FlowJo version 10.5.3 (Tree Star). Isotype controls for each of antibodies were used for separating negative and positive populations and all gates to define cell subsets were based on this method. For cell sorting experiments, all samples were sorted on a BD FACS Fusion system or acquired on a BD FACS Fortessa system (BD Biosciences). In vitro T cell activation assays. Using the “Naïve CD8+T cell Isolation Kit” (Cat. No.130-093-244, Miltenyi Biotec) naïve human CD8+T cells were isolated from peripheral blood mononuclear cells, obtained from blood samples of de-identified donors from the San Diego Blood Bank (SDBB). Subsequently, the naïve CD8+T cells (0.3 x 106per well) were stimulated in a 48-well plate pre-coated with anti-CD3 (1 µg / mL, Cat. No.16-0037-85, eBioscience) and anti-CD28 (1 µg / mL, Cat. No.16-0289-85, eBioscience) in the presence or absence of recombinant human TGF-β (20 ng / mL, Cat. No.240-B, R&D Systems) for 24 hours and 48 hours. Naïve mouse CD8+T cells (CD8+CD44loCD62Lhi) were isolated from spleen, and 0.5 x 106cells were stimulated in a 48-well plate pre-coated with anti-CD3 (1 µg / mL, Cat. No. BE0001-1, BioXCell) and anti-CD28 (1 µg / mL, Cat. No.16-0281-85, eBioscience) in RPMI- 1640 medium supplemented with 10% FBS and TGF-β (10 ng / mL, Cat. No.763102, BioLegend) or mouse IL-15 / IL-15R complex (0.4 ng / mL, Cat. No.50-898-0, Invitrogen) for 24 hours and 48 hours or the indicated time points. 84 4914-9544-4227.1 Atty Docket No.116639-2730 In vivo T cell proliferation assay. Naïve OT-I CD8+T cells (CD8+CD44loCD62Lhi) were purified to > 95% purity from pooled spleens of Gpr25 WT and Gpr25 KO mice using naïve CD8+T cell negative selection kit (Stem Cell Technologies). The cells were labelled with 5 µM Cell Trace Violet (CTV, Cat. No. C34557, Invitrogen) in pre- warmed PBS. Labelling was performed by incubating at 37˚C for 20 min, and the reaction stopped by adding five times the original staining volume of RPMI-1640 medium supplemented with 10% FBS. The cells were incubated for at least 10 min to allow the CTV reagent to undergo acetate hydrolysis. CTV-labelled OT-I cells were then adoptively transferred to recipient mice before infection with 2 x 105PFU LCMV-OVA, and analyzed 24 hours and 48 hours after infection. qRT-PCR. Total RNA was extracted using TRIzol reagent (Cat. No.10296-028, Invitrogen), after which 1.0 µg of total RNA was subjected to cDNA synthesis using a SuperScript Reverse Transcription System (Cat. No.18080-051, Invitrogen). The expression levels of each gene were normalized to Hprt transcript levels. The mouse primer sequences used in the qRT-PCR were as follows: Hprt forward, 5’- CTGGTGAAAAGGACCTCTCGAAG-3’, Hprt reverse, 5’- CCAGTTTCACTAATGACACAAACG-3’, S1pr1 forward, 5'- GTGTAGACCCAGAGTCCTGCG-3', S1pr1 reverse, 5'- AGCTTTTCCTTGGCTGGAGAG-3', Gpr25 forward, 5'- TCACCCTGATCTGCTACTGG-3', Gpr25 reverse, 5'- CGCACTGCTATTGACGAAAGC-3'. The expression levels of human GPR25 were normalized to HPRT1 transcript levels. The human primer sequences used in the qRT-PCR were as follows: HPRT1 forward, 5’- ACCAGTCAACAGGGGACATAA-3’, HPRT1 reverse, 5’- CTTCGTGGGGTCCTTTTCACC-3’, GPR25 forward, 5’- CGCTCATCTACCTCCTGCTG-3’, GPR25 reverse, 5’- ACACGGAACTGTCGTCCCT-3’. Tumor model. OVA-expressing B16F10 (B16F10-OVA) cells were a gift from the J. Linden laboratory (LJI) and tested negatively for mycoplasma infection. Plasmocin (InvivoGen) was used as a routine addition to culture media to prevent mycoplasma contamination. For inducing experimental lung metastasis, 1 x 106B16F10-OVA cells were injected (i.v.) into either naïve mice or mice previously infected with LCMV-OVA. For FTY720 treatment, mice were intraperitoneally injected with FTY720 diluted in sterile PBS at 1mg / kg at indicated time points. Mice were sacrificed on day 14 after injection of tumor cells, and lung 85 4914-9544-4227.1 Atty Docket No.116639-2730 tissues were harvested and subjected to FACS analysis. Lung metastatic nodules present on the surface of the 5 lobes of the lungs per mouse were counted. Single-cell transcriptome assay and analysis. Single-cell transcriptome analysis was performed on cells from two experiments: (i) Liver dataset: Applicant sorted and pooled Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRM cells (CD69+CD62L−KLRG1−) from CD8+T cells in the liver of recipient 8 mice at 30 days post LCMV infection. Prior to infection, congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice, (ii) Lung dataset: Applicant sorted and pooled Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells isolated from lungs of 6 recipient mice at 30 days post infection. Sorted cells were processed using the 10x Genomics 3’ Tag v3.0 chemistry kit following manufacture’s instruction (10x Genomics), and sequenced on Illumina NovaSeq 6000 platform. The sequence data from each library were collapsed into Unique Molecular Identifier (UMI) counts by mapping the reads to the mm10 reference (v3.0.0) using the Cell Ranger (v3.1.0) software (10x Genomics) and aggregated as described78-80. Aggregated data was transferred to the R statistical environment for doublet exclusion and analysis using the Seurat software (v4.1.1)81, as described78-80. To further minimize doublets, Applicant applied Scrublet software82(expected_dublet_rate = 0.06; v0.2.3) and included cells with a doublet score ≤ 0.3 for further analysis. Cells with low-quality transcriptomes and potential remaining doublets were excluded from further analyses based on these criteria: <300 and >5,000 unique genes, <200 and >30,000 total UMI content, and > 10% of mitochondrial UMIs for liver dataset; and <300 and >5,000 unique genes, <200 and >20,000 total UMI content, and > 10% of mitochondrial UMIs for lung dataset. Unbiased clustering analysis was performed using Seurat software (v4.1.1). A first round of clustering analysis was performed and single-cell transcriptomes not meeting quality control thresholds (see above) as well as clusters of contaminating cells characterized by low expression of Cd8b1 were eliminated from the second round of analysis. For both rounds of analysis, only genes expressed in at least 0.1% of the cells were included. Expression counts were then log-normalized and scaled (by a factor of 10,000) per cell. Variable genes were detected with the variance stabilizing transformation (VST) method and most variable genes (UMI mean >0.01) accounting for the tope 25% of the total standardized variance were selected 86 4914-9544-4227.1 Atty Docket No.116639-2730 for downstream analysis. Transcriptomic data from each cell were scaled by regressing the following cell-specific variables: number of UMIs-detected, percentage of mitochondrial UMIs, and cell-cycle score. Principal component analysis (PCA) was performed, and the first 20 principal components (PCs) for both, liver and lung datasets were selected for downstream analysis based on the standard deviation of PCs. Cells were clustered using Seurat’s functions FindNeighbors and FindClusters with a resolution of 0.2 and 0.4 for the liver and lung datasets, respectively. Pairwise single-cell differential gene expression analysis was performed using the R package MAST (v1.14.0)83with cellular detection rate (CDR) as a covariate, after normalizing the data to log2 counts per million (log2(CPM+1)). A gene was considered as differentially expressed if its Benjamini-Hochberg adjusted P-value (called false discovery rate) was <0.05 and log2 fold change was >0.25. Cluster-specific markers were determined by MAST using the Seurat function FindAllMarkers with default parameters. Shape of violin plots represents the distribution of expression (based on a Gaussian Kernel density estimation model) of cells, including cells with no expression. Violin plots are colored according to the percentage of cells expressing the transcript of interest. UMAPs are colored according to the normalized transcript counts of the genes of interest. ATAC-seq data analysis. ATAC-seq data of resting and activated naïve CD8+T cells, TRM and non-TRM CD8+T cells were analyzed as described previously36,84using custom ATAC-seq data processing pipeline ATACproc (https: / / github.com / ay-lab / ATACProc). Briefly, single-end ATAC-seq reads were aligned to hg19 reference genome using Bowtie2 (version 2.3.3.1)85,86, with parameters “-k 4 --mm –threads 8 –X 2000”. Applicant excluded the reads corresponding to mitochondrial genome and chromosome Y. Uniquely mapped reads with mapping quality ≥ 30 were retained using SAMtools (version 1.6)87. Duplicate reads were discarded by Picard tools MarkDuplicates routine (https: / / broadinstitute.github.io / picard). To account for the 9 bp distance between two adapters inserted by the Tn5 transposase88, Applicant then shifted all the reads aligned to the positive (+) strand by +4 bp, and the reads aligned to the negative (-) strand by -5 bp, using deepTools’ “alignmentSieve" routine89. Applicant also discarded reads overlapping with the blacklisted regions (provided in https: / / github.com / Boyle- Lab / Blacklist / tree / master / lists). Coverage tracks were normalized by scaling factor, bins per million mapped reads (BPM), using the “BamCoverage” routine from deepTools89using the arguments “--binSize 50 --normalizeUsing BPM --extendReads”. MACS2 (version 2.1.0)90was 87 4914-9544-4227.1 Atty Docket No.116639-2730 used for peak calling, with parameters: “-g hs –q 0.05 -- nomodel --nolambda --keep-dup all -- call-summits --shift -100 --extsize 200”. UCSC Genome Browser was used to display the tracks. Transcription factor (TF) ChIP-seq data analysis. TF ChIP-seq data for NFATC1, NFATC3 and SMAD1 for GM12878 cells were retrieved from the ENCODE database91. Briefly, reads were aligned using Bowtie2 (version 2.3.3.1)85,86to hg19 reference genome, and coverage tracks were normalized by scaling factor, bins per million mapped reads (BPM), using the “BamCoverage” routine from deepTools89using the arguments “--binSize 10 -- normalizeUsing BPM --extendReads 200”. UCSC Genome Browser was used to display the tracks. Quantification and statistical analysis. Details regarding the number of samples or mice per group, replicates in independent experiments and statistical tests can be found in the figure legends. Sample sizes were based on published studies to ensure sufficient numbers of mice in each group for reliable statistical testing and accounting for variability. The sample sizes are indicated in the figure legends. Age- (8-12 weeks old) and sex-matched mice (female and male) were used in all experiments. For statistical analysis, all experiments, unless stated in figure legends, were performed at least three times independently. Statistical analyses were performed using GraphPad Prism 9 and the statistical tests employed are indicated in the figure legends. Example 3: HTS compatible GPR25 LIFT assay and develop secondary assays to enable a screening cascade to identify antagonists. (i) Generation of a GPR25 LIFT cell line. Site-directed mutagenesis by PCR introduced genetic mutations that replaced tryptophan-164 in GPR25 with alanine (W164A). This mutation disrupts the highly conserved tryptophan residue residing in the fourth transmembrane domain. Similar mutations have been found to cause ER retention of other GPCRs108-110. Although these mutations may ultimately affect receptor function, in this assay they serve the sole purpose of facilitating ER retention of the target. The cDNA constructs encoding mutant GPR25(W164A) were subcloned into an expression vector that encodes a 42- amino acid portion of β-gal, the Pro-link (PK) fragment. Next, GPR25(W164A)-PK are transfected into the PathHunter® U2OS Endosomal-EA (Endo-EA) cells (DiscoverX). These 88 4914-9544-4227.1 Atty Docket No.116639-2730 cells express the remaining portion of the β-gal enzyme fused with the early endosomal protein EEA1. With β-gal split into two fragments: PK and EA, and separated within the cell, no functional β-gal is produced. When brought together they form a functional enzyme capable of converting substrate to light (FIG.13). Stable pools of U2OS-Endo-EA cells expressing GPR25(W164A)-PK are tested for Enzyme Fragment Complementation (EFC) functionality and relative expression of the receptor. Cells are lysed and enzyme substrate together with excess exogenous EA or buffer (No- EA) is added. The excess EA exogenous forces complementation of the β-gal fragments independent of endogenous EA and serves two purposes: (i) to verify integrity and functionality of the reporter; (ii) to provide a relative level of PK-tagged receptor expression. Compared to EA-expressing parental U2OS cells (those lacking a PK-tagged receptor), cells expressing GPR25(W164A)-PK are expected to show high basal activity (no exogenous EA added). Activity increases with the addition of exogenous EA. This determines (i) the fraction of the receptor that migrates to the membrane despite the presence of the ER-retaining mutations, and, more importantly, (ii) the level of increased signal resulting from the addition of exogenous EA, which will demonstrate robust expression of GPR25. Applicant also assesses retention of GPR25(W164A)-PK in the ER using a monoclonal antibody targeting PK, and confocal microscopy. The use of the exogenous EA tag and PK antibody to test the integrity of the assay is an important aspect of applying this technology to understudied receptors, allowing for validation of receptor expression and intracellular localization without a receptor-specific antibody or positive control. (ii) Miniaturization of LIFT assay: Once stable clones are validated, the GPR25- LIFT assay is miniaturized for use in 1536 well plates. The optimal cell-seeding density, DMSO tolerance, and effect of FBS have already been determined for this assay platform from other screens. Positive control. To establish fully a cell-based assay for HTS, one must have a positive control to generate a high signal relative to a negative control or low signal. While this is easy for targets with known ligands like ADRB2, the lack of a known ligand for GPR25 presented a challenge to assay development. A basal level of receptor forward trafficking in the LIFT assay facilitates the use of the proteasome inhibitor bortezomib as a non-specific high-signal control compound. By blocking the cell’s endogenous system for degrading the mutant oGPCR 89 4914-9544-4227.1 Atty Docket No.116639-2730 bortezomib creates a “back-log” in the ER allowing some of the misfolded GPR25 protein to “leak” through. Assay parameters. Stable U2OS LIFT cells expressing the mutant target GPR25 are first dispensed at a range of cell seeding densities (500–1500 cells / well). Bortezomib (10µM) is used to induce trafficking of the mutant oGPCR and produce EFC-derived luminescence. Next, the effect of serum (0.0-10.0% FBS) and DMSO (0.0–2.0% final v / v) on assay performance is determined. The variability of the assay is determined by running triplicate max / mid / min plates on three days and then calculating the Z’ factor112. The minimal performance criteria (Z’ ≥ 0.5, S / N ≥ 2.0, %CV ≤ 10) is required for a HTS. (iii) Using the primary LIFT assay: To confirm the suitability of the primary pharmacochaperone assay developed, a pilot screen consisting of 3 plates (1,536 well) is screened in two independent experiments. Compounds are tested at both 10 and 20 µM final concentration to determine screen concentration and estimate hit rate. The pilot screen consists of library of pharmacologically active compounds (LOPAC), and 3 plates containing diverse chemicals from the SBP GPCR library. (iv) Develop secondary, orthogonal and counter assays: The mutant GPR25 used in the LIFT assay does not occur naturally, its only purpose is to retain the target in the ER, keeping PK separate from the EA until compounds induce forward trafficking (FIG.13). Hits from the primary LIFT assay are confirmed as active on native wild-type GPR25. The signaling of human GPR25 is unknown, but in non-mammalian system it is coupled to Gi-cAMP (activation of the receptor inhibits forskolin-stimulated cAMP production) and results in receptor internalization72. Equivalent assays to monitor these end points in HEK293 under-expressing human wt GPR25 have already been described and characterized72, and these assays are used to evaluate hits identified from the screen. Note, GPR25 CHO-K1 b-arrestin cell lines are commercially available. Applicant establishes the primary HTS assay based on the LIFT platform and develops downstream secondary assays to enable a hit ID testing funnel (FIG.14). 90 4914-9544-4227.1 Atty Docket No.116639-2730 Example 4: GPR25 antagonist lead generation and characterization for functional studies in vitro and in vivo. (i) Elaborate structure-activity relationship (SAR) by medicinal chemistry. To reveal nascent SAR, Applicant starts by purchasing compounds that differ from hits in select chemical groups, which are acquired from trusted commercial vendors. In cases where Applicant is unable to expand the hit set by purchase, Applicant directly begins the process of hit expansion through initiating a classic Hit to Lead medicinal chemistry campaign. Applicant uses the panel of cell-based GPR25 assays to assess potency and selectivity with the goal of optimizing SAR for whole-cell activity. Hit prioritization and expansion efforts leverages the chemistry expertise of Dr. Patrick Kenny (Co-I), the lead medicinal chemist at SBP for the NIH-supported initiative to find chemical probes directed to 10 brain-expressed oGPCRs. Applicant focuses on analogs that show enhanced potency from the original hit, while retaining the same mechanism of action. Applicant performs multiple rounds of analysis of analogs for each hit, and based on this data, additional rounds of analogs are synthesized and tested to define the most critical functional groups responsible for evoking the biological effect at GPR25. After an initial hit expansion phase, Applicant synthesizes analogs at a rate of ~8-10 compounds per month, focused on advancing 2-3 scaffolds to lead status as depicted in FIG.15. (ii) Physiologically-relevant cell based assays. The primary assay that is used to drive SAR will be dose response activity in the GPR25 cAMP TR FRET assay. Due to the homology with APLNR Applicant uses this receptor as a selectivity screen in the SAR campaign, all reagents have already been developed for this receptor at SBP116. As SAR develops and the potency (EC50) of compounds increases below the 1 uM threshold, compounds are evaluated in more physiologically-relevant cell assays. More specifically, Applicant conducts assays on human T cells treated with TGF- β, which induces GPR25 expression (FIG.16), to monitor their effects on activation, proliferation, cytokine release, and their ability to enhance responses to TGF-b. (iii) Determine physicochemical and pharmacological properties for in vivo development. Leads identified in this effort are intended for probing receptor function in cellular systems and with further refinement use in vivo. To assess the drug-like properties of select compounds, Applicant uses a series of standard in vitro ADME / T and physicochemical profiling 91 4914-9544-4227.1 Atty Docket No.116639-2730 assays in place. Briefly, aqueous solubility data are determined at pH 7.4 with UV detection. Lipophilicity is determined using a high-throughput shake-flask method with octanol and water. The cLogD and polar surface area are calculated through use of ChemAxon software. Metabolic stability in human- and mouse-liver microsomes is determined by incubating compounds in 1 mg / mL microsomes; the metabolites are quantitated using liquid chromatography / mass spectroscopy methods. Cellular permeability are determined using a monolayer of MDCK1 cells. Applicant profiles ~25-35 compounds in these assays, and lead compounds with appropriate potency and in vitro ADME properties are dosed (IV / PO / IP) in mice to determine pharmacokinetics. (iv) Lead selection and characterization in vitro and in vivo. The overall testing funnel for identifying lead compound(s) is depicted in FIG.15. Applicant uses all the data generated in the various assays in an ongoing fashion to guide the design of analogs and enhance / evolve the SAR. With each iteration of analog refinement the potency threshold becomes increasingly rigorous. The selection of analogs synthesized in exploring SAR is driven by potency in in vitro cell-based assays, as potency improves this is supplemented by evaluation in more physiologically-relevant T cells assays and increasing emphasis will be placed on developing drug-like properties. Applicant discovers 2-3 leads that are suitable for evaluating activity to enhance lung TRM cell generation in mouse models of viral infection, as described in FIG.5A. Comparing effects of lead antagonist by using Gpr25-sufficient and Gpr25-deficient T cells in vivo enables Applicant to differentiate the effects mediated via Gpr25. Because of high sequence homology, GPR25 antagonists potently activate murine Gpr25. However, if potency is lower, humanized mouse models can be used to determine activity of GPR25 in vivo. Applicant completes lead generation efforts culminating in the identification of 1- 3 hGPR25 antagonist for functional testing in vitro (human T cells) and in vivo (mouse models). Applicant performs comprehensive efficacy and toxicity studies in mouse models for further advancing the drug-development pathway towards clinical testing. Feasibility in an academic setting. Applicant has extensive experience in HTS and lead optimization of screening hits identified from oGPCR LIFT screens. All the in vitro ADME 92 4914-9544-4227.1 Atty Docket No.116639-2730 assays are conducted at SBP on a routine basis, testing dozens of compounds each week, Similarly, pharmacokinetic studies are performed in the Exploratory Pharmacology Core facility at SBP. Example 5: The role of TGF-β signaling in the regulation and function of GPR25 in TRM cells. Although Gpr25 plays a critical role in the development of TRM cells, the mechanisms regulating its expression in T cells in not known. Applicant previously found that the expression of GPR25 was strongly correlated with the expression of several key TRM- associated genes, such as ZNF683 (Hobit), RBPJ, ITGAE (CD103), S1PR1 and S1PR533. Because TGF- β is known to tightly regulate the expression of many TRM-associated genes69, Applicant investigated its role in regulating the expression of GPR25. Applicant found that TGF-β treatment resulted in rapid induction of GPR25 in primary human CD8+ T cells that were polyclonally activated in vitro by using anti-CD3 and ant-CD28 antibodies (FIG.1C). Gpr25 expression was also readily induced by TGF-β in murine CD8+ T cells (FIG.1A). To determine how TGF- β signaling regulates expression of GPR25, Applicant analyzed assay for transposase-accessible chromatin using sequencing (ATAC-seq) profile of the GPR25 locus in human CD8+ T cell subsets33,117. Three regions (C1, C2, C3) upstream of GPR25 transcription start site (TSS) displayed prominent transposase accessible peaks (ATAC-seq peaks) in CD8+ TRM cells compared to cell types not expressing GPR25 like non-TRM cells or circulating naïve CD8+ T cells (FIG.1B, top panel). The C2 region, however, displayed prominent transposase accessibility in activated CD8+ T cells. Applicant’s analysis suggested that these three cis-regulatory regions are likely to be involved in the regulation of GPR25 with C1,2,3 regions associated with TRM cells and C2 region with T cell receptor (TCR) activation. Notably, analysis of ENCODE transcription factor ChIP-seq data118 showed that C1, C2 and C3 cis-regulatory regions bind to nuclear factor of activated T-cells (NFAT) and Suppressor of Mothers Against Decapentaplegic (SMAD)1, key transcription factors downstream of TCR119 and TGF-βsignaling120, respectively, suggesting that expression of GPR25 is likely to be co-regulated by these pathways (FIG.1B, bottom panel). 93 4914-9544-4227.1 Atty Docket No.116639-2730 TGF- β and NFAT Expression Regulation of GPR25. (i) ChIP-sequencing studies. Applicant performs SMAD and NFAT ChIP-seq in T cells. Applicant tests at least two different ChIP-seq grade antibodies for SMAD1 (Diagenode, #C15410274; ThermoFisher #701168), SMAD 2 / 3 (Cell Signaling Technology, #8685S; Abcam, ab208182) and NFATc1 (Cell Signaling Technology, #4389; BioLegend, #649601). Assay conditions. Briefly, ChIP-seq assays are performed in primary human and murine CD8+ T cells, utilizing 10 million cells / per assay. Primary CD8+ T cells are polyclonally activated in vitro by using anti-CD3 and ant-CD28 antibodies, and treated with TGF- β (20ng / ml) for 6 hour and 24 hours. To optimize the ChIP assay conditions for SMAD1 / 2 / 3 and NFAT1c, Applicant varies fixation conditions and post-immunoprecipitation washing steps to improve the signal to noise ratio, which are assessed by ChIP-PCR for enrichment in binding sites known to be occupied by these TFs. With good ChIP-grade antibodies. Applicant’s ChIP-sequencing process, known as ChIPmentation121,122, efficiently prepares libraries from ChIP DNA for sequencing, even from low DNA amounts. Applicant sequences these libraries using the Illumina NovaSeq 6000 platform, generating >40 million 100bp paired-end reads per assay. Analysis. Applicant has extensive experience in analyzing ChIP-seq datasets123- 125. Applicant will follow ENCODE guidelines126 for mapping and peak calling and include independent biological replicates for all ChIP-seq assays to assess the reproducibility. As controls, Applicant includes T cells not treated with TGF-β. These studies confirm if NFAT1c and SMAD proteins bind to C1,C2, or C3 enhancers and / or the promoter of GPR25. (ii) CRISPRi studies. The binding of SMAD proteins or NFAT to cis-regulatory regions (C1,C2,C3) in the GPR25 locus does not imply that SMAD is regulating GPR25 expression. It is important to show that these SMAD-bound regions are indeed functioning as enhancers for GPR25. To demonstrate this, Applicant utilizes CRISPRi (dCas9-KRAB) assays, as described122, to silence the cis-regulatory elements (C1, C2 or C3) that bind SMAD or NFAT in activated CD8+ T cells treated with TGF- β and then determines the effects on GPR25 gene expression by qPCR. As controls, Applicant utilizes non-targeting sgRNAs. Applicant has optimized this assay to work in primary human T cells, and has tested ~10 cis-regulatory elements in a few months, as described in Chandra et al Nature Genetics 2021122.. 94 4914-9544-4227.1 Atty Docket No.116639-2730 To ascertain whether SMAD binding is indispensable for the activity of these enhancers, Applicant will utilize only the catalytically dead Cas9 protein (dCas9) along with tiling guide RNAs to target multiple regions) in and around the predicted SMAD binding sites in C1, C2 or C3 enhancer. Because dCas9 lacks any silencing domain, binds to targeted chromatin with high affinity and effectively prevent the binding of SMAD proteins. Thus enabling us to examine if SMAD binding is required for the activity of GPR25 enhancers. Applicant has extensively used this assay to narrow-down functional SNPs in enhancers (Nature Genetics 2021122). Together, these CRISPR-based assays define the mechanism by which TGF-β positively regulates the expression of GPR25. The role of NFAT, the transcription factor down- stream of TCR signaling, will also be assessed. Results. Applicant determines if SMAD and NFAT proteins bind to the GPR25 locus, implying their potential to directly regulate GPR25 expression. The results demonstrate that the regions bound by SMAD display enhancer activity that is dependent on SMAD binding, thus confirming that GPR25 is a bona-fide target gene of TGF- β. Caveats and alternative approaches. (i) Other transcription factors and pathways may regulate GPR25? While Applicant’s initial focus is on determining whether GPR25 is the direct target genes of SMAD and NFAT, Applicant is aware that other transcription factors and signaling pathway may also play a role. Because IL-15 signaling is important for TRM cell development127-129, Applicant determines if IL-15 induces GPR25 expression. Applicant examines binding of STAT5, down-stream of IL-15 signaling130, to enhancers in the GPR25 locus. (ii) CRISPR-based assays may have lower silencing efficiency at certain genomic regions. Applicant has extensive experience with these assays. Applicant’s also consider guide RNAs targeting nearby regions to improve its efficiency. (iii) Broad silencing with CRISPRi assays. To precisely test if SMAD binding is required for the C1-C3 enhancers to regulate GPR25 expression, Applicant considers CRISPR-mediated homology-directed recombination (HDR) in primary CD8+ T cells to generate isogenic cells with targeted deletion of ~20-30bp SMAD binding site in the GPR25 enhancers. Applicant has performed CRISPR-mediated HDR to test the function of a single nucleotide polymorphism (SNP)122. 95 4914-9544-4227.1 Atty Docket No.116639-2730 Example 5 GPR25 Mediates its effect on TRM cells Applicant’s studies have shown that Gpr25 plays a key role in supporting the development and maintenance of TRM cells in the liver and lungs. However, the signaling pathways and mechanisms though which Gpr25 mediates its effects are not known. Applicant demonstrates Gpr25 modulates TGF- β signaling to influence the development of TRM cells. GPR25 inhibits cAMP signaling. GPR25 is coupled to the Gαi transducer protein that inhibits adenylate cyclase activity and thus reduces cAMP signaling34. Because GPR25 is an orphan GPCR with no known endogenous ligand, effects of ligand-dependent signaling cannot be tested. However, a recent report found that GPR25 exhibited significant ligand- independent i.e., constitutive inhibition of cAMP signaling under both baseline and stimulated conditions (using forskolin, an exogenous agent that activates adenylate cyclase and cAMP signaling)72. Another report showed that non-mammalian vertebrate GPR25 can inhibit cAMP signaling in a ligand-dependent manner131. Based on these data, Applicant reasons that GPR25 signaling is likely to inhibit cAMP pathway and its downstream targets in T cells. cAMP pathway inhibits TGF- β signaling. Studies in other cellular systems has shown then cAMP signaling can inhibit the expression of TGF- β target genes by modulating SMAD signaling132-135. Notably, heightened cAMP signaling activates cAMP-response element binding protein (CREB), which in turn recruits the transcriptional co-activator p300 away from SMADs, thereby restricting the transcriptional activity of SMAD i.e., TGF- β signaling133. TGF- β signaling regulates TRM cell development. The two cytokines, TGF β and IL-15, play central roles in shaping the TRM gene expression programs. TGF β directlyregulates expression of the following key genes55,67,127-130,136-139: (i) CD103, encodes for⍺E integrin, that is expressed by TRM cells at barrier sites; (ii) KLF2, encodes a transcriptionfactor that regulates expression of S1PR1, a sphingosine-1-phosphate receptor that promotes egress of cells from tissues140; (iii) ZEB2, a transcription factor that regulates expression of S1PR5, and (iv) IL-15 receptor (IL-15RA) expression that supports responses to IL-15. 96 4914-9544-4227.1 Atty Docket No.116639-2730 Without being bound by theory, these data support a hypothesis that GPR25, through the inhibition of the cAMP pathway, enhances (releases inhibition of) TGF β signaling, thereby supporting the development of TRM cells. To lend support for this hypothesis, Applicant performed single-cell transcriptome analysis of Gpr25+ / + and Gpr25- / - OT-I memory T cells that were isolated from lung tissue 30 days after LCMV-OVA infection (i.t.) (FIG.5F) . Gene set enrichment analysis showed significant positive enrichment of TGF- β signaling genes in Gpr25+ / + memory T cells when compared to versus Gpr25- / - T cells (not shown). Based on transcriptomic features, OT-I T cells clustered into two major subsets; notably, a greater fraction of Gpr25+ / + versus Gpr25- / - OT-I memory T cells (62% versus 38%) were observed in cluster 0 (FIG.5F, left). Compared to cluster 1, cluster 0 cells that were enriched for Gpr25+ / + T cells expressed lower levels of transcripts encoding for molecules linked to effector properties like perforin, granzyme B, granzyme A, and higher levels of transcripts encoding for molecules linked to stem-like memory properties such as Tcf1 and IL7R (FIG.5F and 5E), which suggested that Gpr25 is likely to promote the formation of long-lived memory cells with stem-like properties as opposed to the differentiation into short-lived effectors. Most notably, T cells in cluster 0 compared to cluster 1 displayed lower expression of transcripts encoding for the transcription factors ZEB2 and S1PR5, a sphingone-1-phosphate receptor that promotes egress of cells from tissues140 (FIG. 5E, 5F). A recent study showed that the robust generation of TRM cells requires down- regulation of transcription factor ZEB2 and its target gene S1PR5 by TGF- β signaling in the tissues55, which in turn promotes sequestration of cells in the tissues. Taken together, it is tempting to speculate that Gpr25 may play a role in the downregulation of ZEB2-S1PR5 axis, potentially by modulating TGF- β signaling and thus favoring the generation of TRM cells in the lungs. Strategy and Methods. To determine if Gpr25 enhances TGF- β signaling in T cells, Applicant performs gain-of-function (forced expression of Gpr25), loss-of-function (Gpr25- / - T cells i.e., genetic knockout) and rescue studies. (i) In vitro studies. While TRM cells express Gpr25, their relatively low abundance in vivo makes it challenging to isolate a sufficient number of cells required for 97 4914-9544-4227.1 Atty Docket No.116639-2730 extensive in vitro studies. Instead, Applicant uses naïve CD8+ T cells for these assays. Because Gpr25 is not expressed by naïve CD8+ T cells, Applicant forces expression of Gpr25 using viral transduction methods. Briefly, mouse Gpr25 cDNA construct was cloned into pMSCV-Thy1.1 retroviral vector. Empty vector or Gpr25 plasmid was transfected into Plat-E cells to generate retroviral supernatants, which was used for transducing activated T cells. Transduced T cells were expanded for 2-3 days in IL-2, and Thy1.1-expressing cells sorted for further functional studies. Applicant achieve 30% transduction efficiency in primary CD8+ T cells (not shown). Assays and Readouts. Here, Applicant treats CD8+ T cells with forced expression of Gpr25 and control T cells (empty vector transduced cells) with TGF- β (20 ng / ml) and compares their responses at different time points (4, 24 and 48 hours) using multiple assays / readouts that include: (a) Flowcytometry and qPCR to assess expression of key TGF-β target genes such as CD103, Klf2, S1pr1, S1pr5, and Zeb2. In addition, Applicant assess if forced expression of Gpr25 in T cells leads to increased expression of TGF- β receptor II (TGF-β R2)141, potentially augmenting TGF- β sensing. (b) Bulk RNA-seq analysis to identify genes that are differentially expressed following forced expression of Gpr25. Perform GSEA to determine if global TGF-β signature genes are enriched in T cells with forced expression of Gpr25. (c) SMAD-ChIP-seq to definitively determine if forced Gpr25 expression in T cells results in enhanced binding of SMAD proteins at the TGF- β target genes (Aim 2A). (ii) In vivo studies. Applicant determines if forced expression of Gpr25 in CD8+ T cells promotes the development of TRM cells by enhancing TGF- β signaling. Applicant transfers congenically distinct OT-1 T cells with forced Gpr25 expression (generated as above), as well as control groups with empty vector expressing cells and Gpr25- / - OT-I T cells, into separate cohorts of mice prior to LCMV infection (as shown in FIG.5). Applicant evaluates the phenotype and transcriptional features of congenically-marked transferred cells in the lungs at day 14 and day 30 following infection. Readouts. (a) Phenotype. Applicant examines expression of marker genes linked to TRM cells (CD69, CD103, CXCR6) and TCM cells (CD62L, CD127); (b) Single-cell RNA-seq, as described in FIG.5F, at early (day 14) and late (day 30) timepoints to determine if forced Gpr25 expression skews the development of memory T cells towards TRM phenotype by restraining the expression of TGF- β target genes that promote tissue egress (Klf2-S1pr1 and Zeb2-S1pr5 axis). Applicant examines if signature genes in TGF- β pathway are enriched in T cells with forced Gpr25 expression. (c) Single-cell ATAC-seq analysis to 98 4914-9544-4227.1 Atty Docket No.116639-2730 determine if forced Gpr25 expression increases chromatin accessibility at key TGF- β signature genes. These results can confirm the hypothesis that Gpr25 mediates its effects by augmenting the TGF- β signaling pathway. (iii) Rescue studies. Gpr25-deficient T cells display defects in TRM cell development (FIG.3-5). If Gpr25 mediates its effects primarily by impairing TGF- β signaling then restoring TGF- β signaling should rescue the phenotype, i.e., development of TRM cells. Here, Applicant forces expression of the constitutively active TGF- β receptor (TGF-β RICA)67,142 in Gpr25-deficient and Gpr25-sufficient (controls) OT-1 T cells and assess its impact on lung TRM cell development in the LCMV-infection model, as described (FIG.5). Constitutively active TGF- β signaling restores the capacity of Gpr25-deficient T cells to develop into lung TRM cells by restricting their capacity to egress from the lungs. Forced expression of Gpr25 results in enhancement of TGF- β signaling in T cells, which is evident through changes in the expression levels, SMAD binding and chromatin accessibility of TGF- β target genes. Are other pathways involved in mediating the effects of Gpr25? Although enhanced TGF- β signaling is Applicant’s primary hypothesis, Applicant’s alternate hypothesis is ‘IL-15 signaling pathway is modulated by Gpr25 to promote TRM development’. The cAMP signaling pathway, which is inhibited by Gpr25, has been shown to inhibit IL-2 and its downstream signaling pathway (JAK3 / STAT5)143. Considering that IL-15 utilizes similar receptors and engages downstream STAT3 / 5 pathway144, it is highly plausible that cAMP may also inhibit IL-15 signaling. Notably, IL-15 signaling has been shown to support the expansion and survival of developing TRM cells127-129, while also inducing the expression of Hobit53, a critical TRM transcription factor that down-regulates expression of genes involved in tissue egress / TCM such as S1PR1 and CCR753. Several studies have shown that IL15 receptor- deficient T cells display profound defects in the development and maintenance of TRM cells in vivo127-129. Based on this rationale, here, Applicant will test if IL-15 signaling pathway is also modulated by Gpr25 (alternative hypothesis). Because of Applicant’s unbiased approaches (RNA-seq, ATAC-seq), Applicant determines if forced expression of Gpr25 impacts target genes and enhancers that are down-stream of IL-15 signaling pathway. In the in vitro models, 99 4914-9544-4227.1 Atty Docket No.116639-2730 Applicant treats T cells with forced expression of Gpr25 and control T cells (empty vector transduced cells) with IL-15 and assess its effects (as for TGF- β), including phosphorylation of STAT5, the key downstream signaling mediator of IL-15. Utilizing Applicant’s unbiased datasets, Applicant is able to determine if Gpr25 modulates the activities of other transcriptional regulators involved in the development of TRM cells such as Blimp-1, Runx3 and Id3. (ii) Lack of endogenous ligand for Gpr25. Given that ligand-independent constitutive activity has been reported for Gpr2572, Applicant observe effects in vitro even in the absence of endogenous ligand. (iii) Organ-specific effects. Due to the critical role of lung TRM cells in infection control and mucosal immunity, Applicant’s focuses on examining the down-stream effects of Gpr25 in lung TRM cells. However, Applicant’s studies have shown that Gpr25 is also important for the development of liver TRM cells. Recent studies have shown that TRM cells in various tissues, such as liver and skin, utilize distinct yet overlapping signaling pathways67. Therefore, Gpr25 may modulate different pathways in liver TRM cells. Example 6: TGF-β Regulates Expression of GRP25 Applicant performs ChIP-seq studies to determine if SMAD proteins, downstream of TGF-β signaling, bind to cis-regulatory elements in the GPR25 locus. Subsequently, Applicant utilizes CRISPR-based assays to assess if SMAD-bound regions enhance the expression of GPR25 in T cells. (B) Applicant’s preliminary studies (FIG.5) support the hypothesis that Gpr25 may modulate TGF- β signaling to influence development of TRM cells. Applicant performs gain-of-function (forced expression of Gpr25), loss-of-function (Gpr25- / - T cells i.e., genetic knockout) and rescue studies (forced expression of constitutively active TGF- β RICA) both in vitro and in vivo, using mouse models of viral infection. Equivalents It is to be understood that while the invention has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains. 100 4914-9544-4227.1 Atty Docket No.116639-2730 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All nucleotide sequences provided herein are presented in the 5′ to 3′ direction. The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification, improvement and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this invention. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control. 101 4914-9544-4227.1 Atty Docket No.116639-2730 Table 1 24 h 48 h TGFβ - TGFβ + TGFβ - TGFβ + 8 1 9 7 2 3 4 842 Table 2 No TGFβ IL-15 3 2 5 7 4 4 8 102 4914-9544-4227.1 Atty Docket No.116639-2730 Table 3 Spleen Liver siIEL CD8 CD69- CD69+ CD8αα CD8αβ 8 2 7 4 6 8 103 4914-9544-4227.1 Atty Docket No.116639-2730 REFERENCES: 1. Schenkel, J. M. & Masopust, D. Tissue-resident memory T cells. Immunity 41, 886-897, doi:10.1016 / j.immuni.2014.12.007 (2014). 2. Kok, L., Masopust, D. & Schumacher, T. N. The precursors of CD8(+) tissue resident memory T cells: from lymphoid organs to infected tissues. Nat Rev Immunol 22, 283- 293, doi:10.1038 / s41577-021-00590-3 (2022). 3. Ganesan, A. P. et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat Immunol 18, 940-950, doi:10.1038 / ni.3775 (2017). 4. Mani, V. et al. 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Claims

Atty Docket No.116639-2730 WHAT IS CLAIMED IS:

1. A method of treating one or more of asthma, an autoimmune disease, or a fibrotic disease in a subject comprising administering to the subject an effective amount of an agent to inhibit the activity of a population of T-cells expressing GPR25, thereby treating the one or more of asthma, the autoimmune disease, or fibrotic disease in the subject.

2. A method of treating one or more of asthma, an autoimmune disease, or a fibrotic disease in a subject comprising administering to the subject an effective amount of an agent that reduces expression of GPR25 in T-cells, thereby treating the one or more of asthma, the autoimmune disease, or the fibrotic disease in the subject.

3. The method of claim 1 or claim 2, wherein the T-cells are CD4+ or CD8+ T-cells.

4. The method of claim 3, wherein the T-cells are CD8+ T-cells.

5. The method of any one of claims 1-4, wherein the T-cells are tissue resident memory (TRM) cells.

6. The method of any one of claims 1-4, wherein the agent is selected from a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA.

7. The method of claim 6, wherein the siRNA or miRNA is complementary to at least a fragment of a polynucleotide encoding GPR25.

8. The method of any one of claims 2 to 7, wherein administration of the agent induces lower than baseline expression of GRP25 in T-cells.

9. The method of claim 8, wherein higher than baseline expression is at least about a 2-fold increase in expression of the one or more genes relative to baseline expression and / or lower than baseline expression is at least about a 2-fold decrease in expression of the one or more genes relative to baseline expression.

10. The method of claim 8 or claim 9, wherein baseline expression comprises normalized mean gene expression. 112 4914-9544-4227.1Atty Docket No.116639-2730 11. The method of any one of claims 1 to 10, further comprising administering to the subject an additional therapy for the one or more of asthma, the autoimmune disease, or the fibrotic disease.

12. The method of claim 11, wherein the additional therapy comprises one or more of bronchodilators, corticosteroids, and / or monoclonal antibodies for the treatment of one or more of asthma, the autoimmune, or the fibrotic disease.

13. A method of diagnosing one or more of asthma, an autoimmune disease, or a fibrotic disease in a subject, comprising contacting a sample isolated from the subject with an agent that detects the presence of GPR25 in the sample isolated from the subject, wherein the presence of the one or more genes at higher than baseline expression levels is a diagnostic indicator of asthma or the autoimmune or the fibrotic disease or wherein the absence of the one or more genes at higher or lower than baseline expression levels is not diagnostic indicator of the one or more of asthma, the autoimmune disease, or the fibrotic disease.

14. The method of claim 13, wherein the sample comprises tissue resident memory cells (TRMs).

15. A method of diagnosing one or more of asthma, an autoimmune disease, or a fibrotic disease in a subject comprising contacting tissue-resident memory cells (TRMs) isolated from the subject or a sample isolated from the subject, with an antibody or agent that recognizes and binds to GPR25 to determine the frequency of TRMs expressing these proteins, wherein a high frequency of TRMs expressing these proteins is diagnostic of the one or more of asthma, the autoimmune disease, or the fibrotic disease.

16. A method of determining the density of tissue-resident memory cells (TRMs) in a sample isolated from a subject comprising measuring expression of GPR25 genes in the sample, wherein higher than baseline expression of the GPR25 indicates higher density of TRMs in the sample. 113 4914-9544-4227.1Atty Docket No.116639-2730 17. A method of determining prognosis of a subject having a one or more of asthma, an autoimmune disease, or a fibrotic disease comprising measuring the density of tissue- resident memory cells (TRM) in a sample isolated from the subject, wherein a low density of TRM indicates a more positive prognosis or wherein a high density of TRM indicates a more negative prognosis, optionally wherein the more negative prognosis comprises a decreased probability in the reduction of symptoms of asthma, the autoimmune, or the fibrotic disease and a lack of low density TRM indicates a more positive prognosis, optionally increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease.

18. A method of determining prognosis of a subject suffering from one or more of asthma, an autoimmune disease, or a fibrotic disease comprising contacting tissue-resident memory cells (TRMs) isolated from the subject with one or more of: an antibody or agent that recognizes and a protein encoded by a GPR25 gene, wherein a low density of TRMs indicates a more positive prognosis or wherein a high density of TRMs indicates a more negative prognosis, optionally wherein the more negative prognosis comprises a decreased probability in the reduction of symptoms of asthma, the autoimmune or the fibrotic disease, and wherein the more positive prognosis comprises an increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease.

19. A method of determining prognosis of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease comprising contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds a protein encoded by a GPR25 gene to determine the frequency of TRMs expressing these proteins, wherein a low density of TRMs indicates a more positive prognosis or wherein a high density of TRMs indicates a more negative prognosis, optionally wherein the more negative prognosis comprises a decreased probability in the reduction of symptoms of the autoimmune or fibrotic disease, and wherein the more 114 4914-9544-4227.1Atty Docket No.116639-2730 positive prognosis comprises an increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease.

20. A method of determining prognosis of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease comprising contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds CD103 to determine the frequency of CD103+ TRMs or an antibody that recognizes and binds a protein encoded by a GPR25 gene to determine the frequency of TRMs expressing the protein, wherein a low density of TRMs indicates a more positive prognosis or wherein a high density of TRMs indicates a more negative prognosis, optionally wherein the more negative prognosis comprises a decreased probability in the reduction of symptoms of asthma, the autoimmune disease, or the fibrotic disease, and wherein the more positive prognosis comprises an increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease.

21. A method of determining the responsiveness of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease to immunotherapy comprising contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds a protein encoded by a GPR25 gene to determine the frequency of TRMs in the subject, wherein a high frequency of TRMs indicates lack of responsiveness to immunotherapy.

22. A method of determining the responsiveness of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease to immunotherapy comprising contacting tissue-resident memory cells (TRMs) isolated from the subject with an antibody or agent that recognizes and binds a protein encoded by a GPR25 gene and, to determine the frequency of TRMs expressing these proteins, wherein a low frequency of TRMs expressing these proteins indicates responsiveness to immunotherapy.

23. A method of determining prognosis of a subject having one or more of asthma, an autoimmune disease, or a fibrotic disease comprising measuring the density of CD103 or 115 4914-9544-4227.1Atty Docket No.116639-2730 a protein encoded by a GPR25 gene in a sample isolated from the subject, wherein a low density of TRM indicates a more positive prognosis or wherein a high density or TRM indicates a more negative prognosis optionally wherein the more negative prognosis comprises a decreased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease and a lack of low density TRM indicates a more positive prognosis, optionally increased probability in the reduction of symptoms of the one or more of asthma, the autoimmune disease, or the fibrotic disease.

24. A method of identifying a subject that will or is likely to respond to one or more of an asthma therapy, an autoimmune therapy, or a fibrotic disease therapy, comprising contacting a sample isolated from the subject with an agent that detects the presence of GPR25 in the sample, wherein the presence of the one or more genes at higher or lower than baseline expression levels indicates that the subject is likely to respond to the one or more of the asthma therapy, the autoimmune therapy, or the fibrotic disease therapy.

25. The method of any one of claims 13, 15, or 24, wherein baseline expression is normalized mean gene expression.

26. The method of claim 25, wherein higher than baseline expression of the one or more genes is at least about a 2-fold increase in expression relative to baseline expression and / or lower than baseline expression of the one or more genes is at least about a 2-fold decrease in expression relative to baseline expression.

27. The method of any one of claims 13 to 26, further comprising administering to a patient in need thereof an asthma therapy, an autoimmune therapy, or a fibrotic disease therapy to the subject.

28. The method of claim 27, wherein the asthma therapy, the autoimmune therapy, or the fibrotic disease therapy is one or more of hormonal therapy, immunotherapy, bronchodilators, corticosteroids, or monoclonal antibodies.

29. The method of any one of claims 13 to 28, wherein sample is contacted with an agent, optionally including a detectable label or tag. 116 4914-9544-4227.1Atty Docket No.116639-2730 30. The method of claim 29, wherein the detectable label or tag comprises a radioisotope, a metal, horseradish peroxidase, alkaline phosphatase, avidin or biotin.

31. The method of claim 29 or 30, wherein the agent comprises a polypeptide that binds to an expression product encoded by the gene, or a polynucleotide that hybridizes to a nucleic acid sequence encoding all or a portion of the gene.

32. The method of claim 31, wherein the polypeptide comprises an antibody, an antigen binding fragment thereof, or a receptor that binds to the gene.

33. The method of claim 32, wherein the antibody is an IgG, IgA, IgM, IgE or IgD, or a subclass thereof.

34. The method of claim 33, wherein the IgG is an IgG1, IgG2, IgG3 or IgG4.

35. The method of any one of claims 32 to 34 wherein the antigen binding fragment is a Fab, Fab’, F(ab’)2, Fv, Fd, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv) or VL or VH.

36. The method of any one of claims 13 to 35, wherein the agent is contacted with the sample in conditions under which it can bind to the protein product it targets.

37. The method of any one of claims 13 to 36, wherein the method comprises detection of the antibody-protein product by immunohistochemistry (IHC), in-situ hybridization (ISH), ELISA, immunoprecipitation, immunofluorescence, chemiluminescence, radioactivity, X-ray, nucleic acid hybridization, protein-protein interaction, immunoprecipitation, flow cytometry, Western blotting, polymerase chain reaction, DNA transcription, Northern blotting and / or Southern blotting.

38. The method of any one of claims 13 to 37, wherein the sample comprises cells, tissue, an organ biopsy, an epithelial tissue, a lung, respiratory or airway tissue or organ, a circulatory tissue or organ, a skin tissue, bone tissue, muscle tissue, head, neck, brain, skin, bone and / or blood sample.

39. The method of any one of claims 1 to 38, wherein the one or more of the asthma or autoimmune disease, or a fibrotic disease comprises polymyositis, vasculitis syndrome, 117 4914-9544-4227.1Atty Docket No.116639-2730 giant cell arteritis, Takayasu arteritis, relapsing, polychondritis, acquired hemophilia A, Still's disease, adult-onset Still's disease, amyloid A amyloidosis, polymyalgia rheumatic, Spondyloarthritides, Pulmonary arterial hypertension, graft-versus-host disease, autoimmune myocarditis, contact hypersensitivity (contact dermatitis), gastro-esophageal reflux disease, erythroderma, Behcet's disease, amyotrophic lateral sclerosis, transplantation, rheumatoid arthritis, juvenile rheumatoid arthritis, malignant rheumatoid arthritis, Drug-Resistant Rheumatoid Arthritis, Neuromyelitis optica, Kawasaki disease, polyarticular or systemic juvenile idiopathic arthritis, psoriasis, nonalcoholic fatty liver disease, primary biliary cholangitis, autoimmune hepatitis, autoimmune kidney disease, chronic obstructive pulmonary disease (COPD), Castleman’s disease, asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic encephalomyelitis, arthritis, arthritis chronica progrediente, reactive arthritis, psoriatic arthritis, enterophathic arthritis, arthritis deformans, rheumatic diseases, spondyloarthropathies, ankylosing spondylitis, Reiter syndrome, hypersensitivity (including both airway hypersensitivity and dermal hypersensitivity), allergies, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, erythema nodosum leprosum, Sjögren’s Syndrome, inflammatory muscle disorders, polychondritis, Wegener's granulomatosis, dermatomyositis, Steven-Johnson syndrome, chronic active hepatitis, myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, Irritable Bowel Syndrome, endocrine ophthalmopathy, scleroderma, Grave’s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, vaginitis, proctitis, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, juvenile diabetes (diabetes mellitus type I), autoimmune haematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia (ITP), autoimmune uveitis, uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, glomerulonephritis (with and without nephrotic syndrome), idiopathic nephrotic syndrome or minimal change nephropathy, inflammatory disease of skin, cornea 118 4914-9544-4227.1Atty Docket No.116639-2730 inflammation, myositis, loosening of bone implants, metabolic disorder, atherosclerosis, dislipidemia, bone loss, osteoarthritis, osteoporosis, periodontal disease of obstructive or inflammatory airways diseases, bronchitis, pneumoconiosis, pulmonary emphysema, acute and hyperacute inflammatory reactions, acute infections, septic shock, endotoxic shock, adult respiratory distress syndrome, meningitis, pneumonia, cachexia wasting syndrome, stroke, herpetic stromal keratitis, dry eye disease, iritis, conjunctivitis, keratoconjunctivitis, Guillain-Barre syndrome, Stiff-man syndrome, Hashimoto's thyroiditis, autoimmune thyroiditis, encephalomyelitis, acute rheumatic fever, sympathetic ophthalmia, Goodpasture’s syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome, Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, atopic dermatitis, eczematous dermatitis, aphthous ulcer, lichen planus, autoimmune alopecia, Vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, sensorineural hearing loss, idiopathic bilateral progressive sensorineural hearing loss, autoimmune polyglandular syndrome type I or type II, immune infertility and immune-mediated infertility.

40. A method of inhibiting the proliferation of TRM cells in a subject, comprising administering an agent that modulates expression of GPR25 to the subject.

41. The method of claim 40, wherein the TRM cells are in the lung tissue or liver tissue of the subject.

42. The method of claim 40, wherein the agent is administered to the lung tissue or liver tissue of the subject.

43. A method of inhibiting the development of stem-like TRM cells in a subject, comprising administering an agent that modulates expression of GPR25 to the subject. 119 4914-9544-4227.1

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