Engineered CD8+ T Cells Targeting MHC Class II Autoantigens
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Solution Overview
Problem
Current treatments for autoimmune diseases like multiple sclerosis and Type 1 diabetes are limited, as CD4+ T cells cannot directly target cells lacking MHC class II expression, such as oligodendrocytes and neurons in MS, and pancreatic islet cells in diabetes, due to the restricted expression patterns of MHC class II molecules.
Innovation Solution
Engineered CD8+ T cells are developed to express a heterologous T cell receptor specific for self-antigens bound to MHC class II, allowing them to recognize and target cells expressing these antigens, thereby inhibiting CD4+ T cell activation and reducing autoimmune inflammation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD4+ T cells are used to recognize self-antigens, then autoimmune response can be initiated, but they cannot directly target cells lacking MHC class II expression
Solution Approach 1:
The patent merges the antigen recognition capability of CD4+ T cells (specificity for self-antigens bound to MHC class II) with the cytotoxic effector functions of CD8+ T cells. This is achieved by transferring TCR genes from autoreactive CD4+ T cells into CD8+ T cells, creating hybrid cells that can recognize antigen-presenting cells with high specificity while simultaneously acquiring the ability to directly eliminate target cells through cytotoxic mechanisms.
Solution Approach 2:
The engineered CD8+ T cells achieve multi-functionality by combining two previously separate immune functions: (1) MHC class II-restricted antigen recognition typically performed only by CD4+ T cells, and (2) direct cytotoxic elimination of target cells typically performed by CD8+ T cells. This universal cell type can now both recognize and directly destroy target cells presenting self-antigens on MHC class II molecules.
2Reliability
If MHC class II expression is restricted to certain cells, then CD4+ T cell activation is controlled, but cells like oligodendrocytes and neurons cannot be directly targeted
Solution Approach 1:
The patent uses antigen-presenting cells expressing MHC class II molecules as intermediaries to bridge the gap between CD4+ T cell specificity and direct tissue cell targeting. The engineered CD8+ T cells recognize and eliminate these APCs that present self-antigens, thereby indirectly affecting the tissue-specific target cells (oligodendrocytes, neurons, or pancreatic islet cells) that cannot be directly recognized by T cells.
3Object-affected harmful factors
If conventional immunosuppression is used to treat autoimmune diseases, then inflammation is reduced, but general immune function is suppressed
Solution Approach 1:
The engineered CD8+ T cells exhibit local quality by being highly specific for self-antigens presented on MHC class II molecules. Rather than causing general immunosuppression, they selectively eliminate only the antigen-presenting cells displaying the specific self-antigens associated with the autoimmune disease, thereby reducing inflammation locally at the site of autoimmune pathology while preserving general immune function elsewhere.
Data Source
AI summary
Provided herein are compositions comprising engineered CD8+ T cells that express a heterologous T cell receptor (TCR) having specificity for an autoantigen bound to a Major Histocompatibility Complex (MHC) Class II. Also provided are methods for the treatment of an autoimmune disease comprising administering the engineered CD8+ T cells. Also provided are methods for generating engineered CD8+ T cells that express a heterologous MHC Class II TCR, including methods of isolating autoantigen-MHC class II specific TCR for use in engineering CD8+ T cells for treatment.