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.