The Journal of experimental medicine, Volume 217, Issue 10, 01 October 2020 Liver X receptors are required for thymic resilience and T cell output. Chan CT, Fenn AM, Harder NK, Mindur JE, McAlpine CS, Patel J, Valet C, Rattik S, Iwamoto Y, He S, Anzai A, Kahles F, Poller WC, Janssen H, Wong LP, Fernandez-Hernando C, Koolbergen DR, van der Laan AM, Yvan-Charvet L, Sadreyev RI, Nahrendorf M, Westerterp M, Tall AR, Gustafsson JA, Swirski FK
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. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ's functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ's indispensable roles in adaptive immunity.