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

ABSTRACT

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. LXRαß-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαß's functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαß for cholesterol efflux, thymic epithelial cells (TECs) use LXRαß for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαß protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαß limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαß governs T lymphocyte education and illuminate LXRαß's indispensable roles in adaptive immunity.