Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 217, Issue 10, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20200318
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Funding
- National Institutes of Health [R35 HL135752, P01 HL131478, P01 HL142494]
- American Heart Association Established Investigator Award [17EIA33410439]
- Patricia and Scott EstonMGH Research Scholar
- American Heart Association Postdoctoral Fellowship [AHA 19POST34380057]
- Boehringer Ingelheim Fonds
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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.
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