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.
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December 29 2020
Nuclear receptor LXRβ controls fitness and functionality of activated T cells
Anthony J. Michaels,
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY
2
Immunology and Microbial Pathogenesis Graduate Program, Weill-Cornell Graduate School for Medical Sciences, New York, NY
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Clarissa Campbell,
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY
Correspondence to Alexander Y. Rudensky: rudenska@mskcc.org
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Regina Bou-Puerto,
Regina Bou-Puerto
Investigation, Visualization, Writing - review & editing
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY
2
Immunology and Microbial Pathogenesis Graduate Program, Weill-Cornell Graduate School for Medical Sciences, New York, NY
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Alexander Y. Rudensky
Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing - review & editing
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY
2
Immunology and Microbial Pathogenesis Graduate Program, Weill-Cornell Graduate School for Medical Sciences, New York, NY
Clarissa Campbell: campbec2@mskcc.org
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Anthony J. Michaels
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY
2
Immunology and Microbial Pathogenesis Graduate Program, Weill-Cornell Graduate School for Medical Sciences, New York, NY
Clarissa Campbell
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY
Regina Bou-Puerto
Investigation, Visualization, Writing - review & editing
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY
2
Immunology and Microbial Pathogenesis Graduate Program, Weill-Cornell Graduate School for Medical Sciences, New York, NY
Alexander Y. Rudensky
Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing - review & editing
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY
2
Immunology and Microbial Pathogenesis Graduate Program, Weill-Cornell Graduate School for Medical Sciences, New York, NY
Correspondence to Alexander Y. Rudensky: rudenska@mskcc.org
Clarissa Campbell: campbec2@mskcc.org
*
A.J. Michaels and C. Campbell contributed equally to this paper.
Received:
June 23 2020
Revision Received:
September 16 2020
Accepted:
November 16 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
Memorial Sloan-Kettering Cancer Center
(NO AWARD)
National Cancer Institute
(P30 CA008748, F31 CA254325-01)
National Institute of Allergy and Infectious Diseases
(RO1 AI034206)
Parker Institute for Cancer Immunotherapy
(NO AWARD)
© 2020 Michaels et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (4): e20201311.
Article history
Received:
June 23 2020
Revision Received:
September 16 2020
Accepted:
November 16 2020
Citation
Anthony J. Michaels, Clarissa Campbell, Regina Bou-Puerto, Alexander Y. Rudensky; Nuclear receptor LXRβ controls fitness and functionality of activated T cells. J Exp Med 5 April 2021; 218 (4): e20201311. doi: https://doi.org/10.1084/jem.20201311
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