Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function
FOXP3+ regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naïve and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg c...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/78738 |
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| author | Valentina Stolz Rafael de Freitas e Silva Ramona Rica Ci Zhu Teresa Preglej Patricia Hamminger Daniela Hainberger Marlis Alteneder Lena Müller Monika Waldherr Darina Waltenberger Anastasiya Hladik Benedikt Agerer Michael Schuster Tobias Frey Thomas Krausgruber Sylvia Knapp Clarissa Campbell Klaus Schmetterer Michael Trauner Andreas Bergthaler Christoph Bock Nicole Boucheron Wilfried Ellmeier |
| author_facet | Valentina Stolz Rafael de Freitas e Silva Ramona Rica Ci Zhu Teresa Preglej Patricia Hamminger Daniela Hainberger Marlis Alteneder Lena Müller Monika Waldherr Darina Waltenberger Anastasiya Hladik Benedikt Agerer Michael Schuster Tobias Frey Thomas Krausgruber Sylvia Knapp Clarissa Campbell Klaus Schmetterer Michael Trauner Andreas Bergthaler Christoph Bock Nicole Boucheron Wilfried Ellmeier |
| author_sort | Valentina Stolz |
| collection | DOAJ |
| description | FOXP3+ regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naïve and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg cells. NCOR1-deficient Treg cells failed to protect mice from severe weight loss and intestinal inflammation associated with CD4+ T cell transfer colitis, indicating impaired suppressive function. NCOR1 controls the transcriptional integrity of Treg cells, since effector gene signatures were already upregulated in naïve NCOR1-deficient Treg cells while effector NCOR1-deficient Treg cells failed to repress genes associated with naïve Treg cells. Moreover, genes related to cholesterol homeostasis including targets of liver X receptor (LXR) were dysregulated in NCOR1-deficient Treg cells. However, genetic ablation of LXRβ in T cells did not revert the effects of NCOR1 deficiency, indicating that NCOR1 controls naïve and effector Treg cell subset composition independent from its ability to repress LXRβ-induced gene expression. Thus, our study reveals that NCOR1 maintains naïve and effector Treg cell states via regulating their transcriptional integrity. We also reveal a critical role for this epigenetic regulator in supporting the suppressive functions of Treg cells in vivo. |
| format | Article |
| id | doaj-art-99b838b47ea54f90b5aa68be8607b3a8 |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-99b838b47ea54f90b5aa68be8607b3a82025-08-20T02:12:02ZengeLife Sciences Publications LtdeLife2050-084X2024-10-011310.7554/eLife.78738Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector functionValentina Stolz0Rafael de Freitas e Silva1Ramona Rica2https://orcid.org/0000-0001-5501-8513Ci Zhu3Teresa Preglej4Patricia Hamminger5Daniela Hainberger6Marlis Alteneder7Lena Müller8Monika Waldherr9Darina Waltenberger10Anastasiya Hladik11Benedikt Agerer12Michael Schuster13Tobias Frey14https://orcid.org/0000-0002-6274-9864Thomas Krausgruber15https://orcid.org/0000-0002-1374-0329Sylvia Knapp16https://orcid.org/0000-0001-9016-5244Clarissa Campbell17Klaus Schmetterer18https://orcid.org/0000-0001-9328-4871Michael Trauner19Andreas Bergthaler20Christoph Bock21https://orcid.org/0000-0001-6091-3088Nicole Boucheron22Wilfried Ellmeier23https://orcid.org/0000-0001-8192-8481Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Vienna, Department of Medicine I, Laboratory of Infection Biology, Vienna, AustriaCeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaCeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaMedical University of Vienna, Department of Laboratory Medicine, Vienna, AustriaCeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Medical University of Vienna, Center for Medical Statistics, Informatics, and Intelligent Systems, Institute of Artificial Intelligence, Vienna, AustriaMedical University of Vienna, Vienna, Department of Medicine I, Laboratory of Infection Biology, Vienna, AustriaCeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaMedical University of Vienna, Department of Laboratory Medicine, Vienna, AustriaMedical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Hans Popper Laboratory of Molecular Hepatology, Vienna, AustriaCeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Medical University of Vienna, Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Vienna, AustriaCeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Medical University of Vienna, Center for Medical Statistics, Informatics, and Intelligent Systems, Institute of Artificial Intelligence, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaFOXP3+ regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naïve and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg cells. NCOR1-deficient Treg cells failed to protect mice from severe weight loss and intestinal inflammation associated with CD4+ T cell transfer colitis, indicating impaired suppressive function. NCOR1 controls the transcriptional integrity of Treg cells, since effector gene signatures were already upregulated in naïve NCOR1-deficient Treg cells while effector NCOR1-deficient Treg cells failed to repress genes associated with naïve Treg cells. Moreover, genes related to cholesterol homeostasis including targets of liver X receptor (LXR) were dysregulated in NCOR1-deficient Treg cells. However, genetic ablation of LXRβ in T cells did not revert the effects of NCOR1 deficiency, indicating that NCOR1 controls naïve and effector Treg cell subset composition independent from its ability to repress LXRβ-induced gene expression. Thus, our study reveals that NCOR1 maintains naïve and effector Treg cell states via regulating their transcriptional integrity. We also reveal a critical role for this epigenetic regulator in supporting the suppressive functions of Treg cells in vivo.https://elifesciences.org/articles/78738T lymphocyte subsetsregulatory T cellsautoimmunity |
| spellingShingle | Valentina Stolz Rafael de Freitas e Silva Ramona Rica Ci Zhu Teresa Preglej Patricia Hamminger Daniela Hainberger Marlis Alteneder Lena Müller Monika Waldherr Darina Waltenberger Anastasiya Hladik Benedikt Agerer Michael Schuster Tobias Frey Thomas Krausgruber Sylvia Knapp Clarissa Campbell Klaus Schmetterer Michael Trauner Andreas Bergthaler Christoph Bock Nicole Boucheron Wilfried Ellmeier Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function eLife T lymphocyte subsets regulatory T cells autoimmunity |
| title | Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function |
| title_full | Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function |
| title_fullStr | Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function |
| title_full_unstemmed | Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function |
| title_short | Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function |
| title_sort | nuclear receptor corepressor 1 controls regulatory t cell subset differentiation and effector function |
| topic | T lymphocyte subsets regulatory T cells autoimmunity |
| url | https://elifesciences.org/articles/78738 |
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