Treatment of autoimmune disorders and infections using antagonists of sgk1 activity
a technology of sgk1 activity and autoimmune disorders, which is applied in the direction of enzyme inhibitor ingredients, antibody medical ingredients, peptide/protein ingredients, etc., can solve the problems of autoimmune disease or cancer patients, patients who have received organ transplants, and are susceptible to infections, so as to enhance the th1-mediated immune response in the subject, the effect of enhancing the th1-mediated immune respons
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example 1
[0073]In an effort to determine the mechanism by which mTOR regulates T cell fate, mice were generated in which SGK1 was selectively deleted in T cells. SGK1 floxed mice (A. Fejes-Toth) were bred to CD4-Cre mice, leading to the deletion of SGK1 in T cells, hereafter referred to as T-SGK1− / − mice (FIG. 2). Naïve T cells from Wt, T-Rictor− / − and T-SGK1− / − mice were stimulated with anti-CD3 anti-CD28 and immunoblotted to assay for activity of TORC1 and TORC2 substrates upon TCR engagement (FIG. 3A). Upon stimulation, Wt CD4+ T cells display enhanced mTORC2 activity, as measured by phosphorylation of Akt at serine 473. A selective defect in Akt S473 phosphorylation was observed in T-Rictor− / − mice, which completely lack mTORC2 activity, but this decrease in Akt activity was not observed in T-SGK1− / − mice, indicating that SGK1 functions in a pathway that is downstream of TORC2, yet parallel to Akt. It was previously shown by the inventors that loss of mTORC2 promotes hyperactivation of m...
example 2
[0075]Determination of the functional consequences of deleting SGK1 in CD4+ T cells. Unlike T-Rictor− / − mice, which have a normal lymphocyte compartment, fewer CD3+ T cells were observed in the spleen and lymph nodes of T-SGK1− / − mice (FIGS. 4, 5). Furthermore, T-SGK1− / − mice had a reduced ratio of CD4+ relative to CD8+ T cells in peripheral lymphoid organs. Despite this reduction in the percentages of T cells, T-SGK1− / − mice have similar percentages of natural regulatory T cells and IL-17 producing CD4+ cells in Peyer's patches of the small intestine (FIGS. 6, 7). In addition to their reduced number of T cells, it was also found that CD4+ T cells from T-SGK1− / − mice displayed a slightly reduced rate of proliferation when stimulated with anti-CD3 and irradiated autologous antigen presenting cells (APCs) (FIG. 8). Despite their reduced proliferation, it was found that CD4+ T cells from T-SGK1− / − mice displayed robust cytokine production.
[0076]Like T-Rictor− / − mice, T-SGK1− / − mice con...
example 3
[0077]The determination of the biochemical mechanism by which SGK1 reciprocally regulates Th1 and Th2 differentiation. The inventors have previously shown that CD4+ T cells from T-Rictor− / − mice show diminished phosphorylation of STAT6 in response to IL-4. However, when CD4+ T cells from T-SGK1− / − mice were treated with IL-4, phosphorylation of STAT6 at tyrosine 641 was observed (FIG. 10), suggesting that SGK1 was regulating Th2 differentiation via some other mechanism. Previous studies on the role of SGK1 in renal epithelial cells have demonstrated that SGK1 negatively regulates the HECT-type E3 ligase neural precursor cell expressed, developmentally down-regulated gene 4-like (NEDD4L) by phosphorylation at serine 342 and serine 448. A closely related homolog of NEDD4L is the ubiquitin ligase Itch, which has been shown to interact with the Nedd4 family-interacting protein 1 (Ndfip1) adapter protein to mediate polyubiquitination of JunB, a transcription factor that is essential for ...
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