Nuclear receptor LXRβ controls fitness and functionality of activated T cells

J Exp Med. 2021 Apr 5;218(4):e20201311. doi: 10.1084/jem.20201311.


T cells increase cholesterol biosynthesis upon activation to generate substrates for cellular growth and proliferation. The ubiquitously expressed liver X receptor β (LXRβ) encoded by the Nr1h2 gene is a critical regulator of cholesterol homeostasis in mammalian cells; however, its cell-intrinsic role in T cell biology remains poorly understood. We report that ablation of LXRβ in T cells leads to spontaneous T cell activation and T lymphocytopenia. Unexpectedly, analysis of mixed bone marrow chimeric mice revealed a cell-autonomous survival defect that reduced the fitness of LXRβ-deficient effector T cells, suggesting that the heightened immune activation in mice harboring LXRβ-deficient T cells was due to impaired regulatory T (T reg) cell functionality. Indeed, we found that single-copy deletion of Nr1h2 in T reg cells disrupted activated T reg cell metabolism and fitness and resulted in early-onset fatal autoimmune disease. Our study demonstrated an indispensable requirement for T reg cell-intrinsic LXRβ function in immune homeostasis and provides a basis for immunological therapies through targeting of this receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology*
  • Cells, Cultured
  • Cholesterol / metabolism
  • Female
  • Forkhead Transcription Factors / genetics
  • Homeostasis / genetics
  • Homeostasis / immunology*
  • Liver X Receptors / genetics
  • Liver X Receptors / physiology*
  • Lymphocyte Activation / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Radiation Chimera / immunology
  • Signal Transduction / genetics
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytopenia, Idiopathic CD4-Positive / genetics
  • T-Lymphocytopenia, Idiopathic CD4-Positive / immunology*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Liver X Receptors
  • Nr1h2 protein, mouse
  • Cholesterol