2. Academic Validation
  3. Liver X receptors are required for thymic resilience and T cell output

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

  • J Exp Med. 2020 Oct 5;217(10):e20200318. doi: 10.1084/jem.20200318.
Christopher T Chan 1,  Ashley M Fenn 1,  Nina K Harder 1,  John E Mindur 1,  Cameron S McAlpine 1,  Jyoti Patel 1,  Colin Valet 1,  Sara Rattik 1,  Yoshiko Iwamoto 1,  Shun He 1,  Atsushi Anzai 1,  Florian Kahles 1,  Wolfram C Poller 1,  Henrike Janssen 1,  Lai Ping Wong 2,  Carlos Fernandez-Hernando 3,  David R Koolbergen 4,  Anja M van der Laan 5,  Laurent Yvan-Charvet 6 7,  Ruslan I Sadreyev 8,  Matthias Nahrendorf 1,  Marit Westerterp 7 9,  Alan R Tall 7,  Jan-Ake Gustafsson 10,  Filip K Swirski 1
Affiliations

Affiliations

  • 1 Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
  • 2 Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA.
  • 3 Vascular Biology and Therapeutics Program, Department of Comparative Medicine and Pathology, Yale University School of Medicine, New Haven, CT.
  • 4 Heart Center, Department of Cardiothoracic Surgery, Amsterdam Universitair Medische Centra, University of Amsterdam, Amsterdam, Netherlands.
  • 5 Heart Center, Department of Cardiology, Amsterdam Universitair Medische Centra, University of Amsterdam, Amsterdam, Netherlands.
  • 6 Institut National de la Santé et de la Recherche Médicale, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire, Atip-Avenir, Fédération Hospitalo-Universitaire Oncoage, Nice, France.
  • 7 Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY.
  • 8 Department of Molecular Biology and Department of Pathology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA.
  • 9 Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
  • 10 Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX.
PMID: 32716519 DOI: 10.1084/jem.20200318
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.

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