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

Abstract

Major histocompatibility complex (MHC) class II-reactive CD8+ Tcells 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+ Tcells reactive to both MHC class I and II molecules in MHC class II-deficient mice. We clone their Tcell 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+ Tcells. When encountering MHC class II in the periphery, they undergo robust activation and proliferation, attack self-tissues, and cause lethal autoimmune diseases. In adoptive Tcell therapy, those CD8+ Tcells are able to efficiently control MHC class II-expressing tumors. This study opens the door to investigation of dual-reactive CD8+ Tcells, their development and selection in the thymus, and the perils and promises when their normal development and selection are compromised.