Liver X receptors are required for thymic resilience and T cell output

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)-a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity-critically contribute to thymic integrity and function. LXR alpha beta-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXR alpha beta's functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXR alpha beta for cholesterol efflux, thymic epithelial cells (TECO use LXR alpha beta for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXR alpha beta protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXR alpha beta limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXR alpha beta governs T lymphocyte education and illuminate LXR alpha beta's indispensable roles in adaptive immunity.