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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
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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. |
format | Online Article Text |
id | pubmed-7774588 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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