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MHC II regulation of CD8+ T cell tolerance and implications in autoimmunity and cancer immunotherapy

ABSTRACT: Previous studies suggested the presence of MHC class II-reactive CD8+ T cells in humans and animals, but little is known about their identity, development and function. In this study, we discovered a group of CD8+ T cells bearing T cell receptors (TCRs) reactive to both MHC I and II molecules in MHC II-deficient mice. We cloned their TCRs and analyzed their development and function. In wild type animals, thymocytes bearing those TCRs were purged by negative selection. In the absence of MHC II, they developed into CD8+ T cells and entered the peripheral T cell pool. When encountering MHC II in the periphery, they underwent robust activation and proliferation, attacked self-tissues, and caused lethal autoimmune diseases. In adoptive T cell therapy, CD8+ T cells bearing those TCRs were able to efficiently control MHC II-expressing tumors. This study opens the door to investigate dual-reactive CD8+ T cells, their development and selection in the thymus, and the peril and promise when their normal development and selection are compromised.

ORGANISM(S): Mus musculus

PROVIDER: GSE245767 | GEO | 2023/10/22

REPOSITORIES: GEO

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Project description:Background Clinical success of T cell receptor (TCR) gene therapy has previously been demonstrated for NY-ESO-1 TCR gene therapy. To increase numbers of cancer patients that can be treated with TCR gene therapy we aimed to identify a novel set of high-affinity cancer specific TCRs targeting different cancer testis (CT) antigens in prevalent HLA class I alleles. Methods In this study, we selected based on publicly available gene expression databases the most promising CT genes to target. From these selected genes we identified by HLA peptidomics the naturally processed and presented HLA class I peptides. With these peptide-HLA tetramers were generated, and by single cell sorting CT specific CD8+ T cells were selected, and expanded from the allo-HLA repertoire of healthy donors. By several functional assays high avidity CT-specific T cell clones with safe recognition pattern were selected. To evaluate the potential for clinical application in TCR gene therapy, TCRs were sequenced and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 in the context of human leukocyte antigen(HLA) -A1, -A2, -A3, -B7, -B35 and -C7. TCR gene transfer into CD8⁺ T cells resulted in efficient cytokine production and cytotoxicity of variety of different tumor types without detectable cross-reactivity. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells was observed in an orthotopic xenograft model for established multiple myeloma, in which bone marrow located tumor cells were completely eradicated after T cell injection. Conclusion The identification of 7 novel CT-specific TCRs, reactive against CT antigens presented in a variety of different HLA class I alleles, allows selection of therapeutic TCRs for an increased number of cancer patients, and will improve development of personalized TCR gene therapy.

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MHC II regulation of CD8+ T cell tolerance and implications in autoimmunity and cancer immunotherapy

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