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
  • 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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