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

Christopher T. Chan, Ashley M. Fenn, Nina K. Harder, John E. Mindur, Cameron S. McAlpine, Jyoti Patel, Colin Valet, Sara Rattik, Yoshiko Iwamoto, Shun He, Atsushi Anzai, Florian Kahles, Wolfram C. Poller, Henrike Janssen, Lai Ping Wong, Carlos Fernandez-Hernando, David R. Koolbergen, Anja M.Van Der Laan, Laurent Yvan-Charvet, Ruslan I. SadreyevMatthias Nahrendorf, Marit Westerterp, Alan R. Tall, Jan Ake Gustafsson, Filip K. Swirski

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

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. 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.

Original languageEnglish
Article number20200318
JournalJournal of Experimental Medicine
Volume217
Issue number10
DOIs
Publication statusPublished - 2020 Jul
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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