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

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. Naïve CD8 T cells were isolated from WT or MHC II-/- mice, labeled with CTV, adoptively transferred into 15 irradiated B6 mice respectively, with one million CD8 T cells per mouse. Splenocytes were isolated and CTV- fast-proliferating cells were sorted. All 0.02 million CTV- WT CD8 T cells sorted and 0.15 million out of 1.2 million CTV- MHC II-/- CD8 T cells sorted were subjected to 10x genomics TCR sequencing.