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Nuclear receptor LXRβ controls fitness and functionality of activated T cells

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 ro...

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Autores principales: Michaels, Anthony J., Campbell, Clarissa, Bou-Puerto, Regina, Rudensky, Alexander Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774588/
https://www.ncbi.nlm.nih.gov/pubmed/33373442
http://dx.doi.org/10.1084/jem.20201311
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author Michaels, Anthony J.
Campbell, Clarissa
Bou-Puerto, Regina
Rudensky, Alexander Y.
author_facet Michaels, Anthony J.
Campbell, Clarissa
Bou-Puerto, Regina
Rudensky, Alexander Y.
author_sort Michaels, Anthony J.
collection PubMed
description 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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spelling pubmed-77745882021-10-05 Nuclear receptor LXRβ controls fitness and functionality of activated T cells Michaels, Anthony J. Campbell, Clarissa Bou-Puerto, Regina Rudensky, Alexander Y. J Exp Med Brief Definitive Report 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. Rockefeller University Press 2020-12-29 /pmc/articles/PMC7774588/ /pubmed/33373442 http://dx.doi.org/10.1084/jem.20201311 Text en © 2020 Michaels et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/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/).
spellingShingle Brief Definitive Report
Michaels, Anthony J.
Campbell, Clarissa
Bou-Puerto, Regina
Rudensky, Alexander Y.
Nuclear receptor LXRβ controls fitness and functionality of activated T cells
title Nuclear receptor LXRβ controls fitness and functionality of activated T cells
title_full Nuclear receptor LXRβ controls fitness and functionality of activated T cells
title_fullStr Nuclear receptor LXRβ controls fitness and functionality of activated T cells
title_full_unstemmed Nuclear receptor LXRβ controls fitness and functionality of activated T cells
title_short Nuclear receptor LXRβ controls fitness and functionality of activated T cells
title_sort nuclear receptor lxrβ controls fitness and functionality of activated t cells
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774588/
https://www.ncbi.nlm.nih.gov/pubmed/33373442
http://dx.doi.org/10.1084/jem.20201311
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