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

Major histocompatibility complex (MHC) class II-reactive CD8+ T cells are found in humans and animals, but little is known about their identity, development, and function. In this study, we discover a group of CD8+ T cells reactive to both MHC class I and II molecules in MHC class II-deficient mice. We clone their T cell receptors (TCRs) and analyze their development and function. In wild-type animals, thymocytes bearing those TCRs are purged by negative selection. In the absence of MHC class II, they develop into mature CD8+ T cells. When encountering MHC class II in the periphery, they undergo robust activation and proliferation, attack self-tissues, and cause lethal autoimmune diseases. In adoptive T cell therapy, those CD8+ T cells are able to efficiently control MHC class II-expressing tumors. This study opens the door to investigation of dual-reactive CD8+ T cells, their development and selection in the thymus, and the perils and promises when their normal development and selection are compromised. [Display omitted] •MHC class II plays critical roles in central tolerance of CD8+ T cells•MHC class I and II dual-specific CD8+ T cells escape negative selection in MHC class II-deficient mice•Dual-specific CD8+ T cells cause autoimmunity when encountering MHC class II molecules•Dual-specific CD8+ T cells potently kill MHC class II-expressing tumor cells Zhou et al. discover a group of MHC class I and II dual-specific CD8+ T cells in MHC class II-deficient animals. Those CD8+ T cells cause autoimmunity when encountering MHC class II molecules in the periphery and potently kill MHC class II-expressing tumor cells.