Thymic resilience and T cell output require Liver X Receptors

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here we show that liver X receptors, which are a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity, critically contribute to thymic integrity and function. LXRaß-deficient mice develop a fatty, rapidly-involuting thymus, and acquire a shrunken and prematurely senescent peripheral T cell repertoire. The functions of LXRaß are cell specific and the resulting phenotypes mutually independent. Whereas macrophages require LXRaß for reverse cholesterol transport and lipid removal, thymic epithelial cells (TEC) and thymocytes respectively utilize LXRaß for self-renewal and negative selection. Consequently, TEC-derived LXRaß protect against premature involution in homeostasis and orchestrate thymic regeneration following stress, while thymocyte-derived LXRaß limit cell disposal during negative selection and confer heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRaß govern T lymphocyte education. Overall design: Cortical and medullary thymic epithelial cells sorted from LXRalpha-flox LXRbeta-flox control versus FoxN1-Cre LXRalpha-flox LXRbeta-flox (4 total groups)