ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance
Objective: Regulatory T cells (Tregs) are essential in maintaining immune tolerance and controlling inflammation. Treg stability relies on transcriptional and post-translational mechanisms, including histone acetylation at the Foxp3 locus and FoxP3 protein acetylation. Additionally, Tregs depend on...
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Elsevier
2025-04-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000183 |
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| author | Philipp Stüve Gloria J. Godoy Fernando N. Ferreyra Florencia Hellriegel Fatima Boukhallouk Yu-San Kao Tushar H. More Anne-Marie Matthies Tatiana Akimova Wolf-Rainer Abraham Volkhard Kaever Ingo Schmitz Karsten Hiller Matthias Lochner Benoît L. Salomon Ulf H. Beier Michael Rehli Tim Sparwasser Luciana Berod |
| author_facet | Philipp Stüve Gloria J. Godoy Fernando N. Ferreyra Florencia Hellriegel Fatima Boukhallouk Yu-San Kao Tushar H. More Anne-Marie Matthies Tatiana Akimova Wolf-Rainer Abraham Volkhard Kaever Ingo Schmitz Karsten Hiller Matthias Lochner Benoît L. Salomon Ulf H. Beier Michael Rehli Tim Sparwasser Luciana Berod |
| author_sort | Philipp Stüve |
| collection | DOAJ |
| description | Objective: Regulatory T cells (Tregs) are essential in maintaining immune tolerance and controlling inflammation. Treg stability relies on transcriptional and post-translational mechanisms, including histone acetylation at the Foxp3 locus and FoxP3 protein acetylation. Additionally, Tregs depend on specific metabolic programs for differentiation, yet the underlying molecular mechanisms remain elusive. We aimed to investigate the role of acetyl-CoA carboxylase 1 (ACC1) in the differentiation, stability, and function of regulatory T cells (Tregs). Methods: We used either T cell-specific ACC1 knockout mice or ACC1 inhibition via a pharmacological agent to examine the effects on Treg differentiation and stability. The impact of ACC1 inhibition on Treg function was assessed in vivo through adoptive transfer models of Th1/Th17-driven inflammatory diseases. Results: Inhibition or genetic deletion of ACC1 led to an increase in acetyl-CoA availability, promoting enhanced histone and protein acetylation, and sustained FoxP3 transcription even under inflammatory conditions. Mice with T cell-specific ACC1 deletion exhibited an enrichment of double positive RORγt+FoxP3+ cells. Moreover, Tregs treated with an ACC1 inhibitor demonstrated superior long-term stability and an enhanced capacity to suppress Th1/Th17-driven inflammatory diseases in adoptive transfer models. Conclusions: We identified ACC1 as a metabolic checkpoint in Treg biology. Our data demonstrate that ACC1 inhibition promotes Treg differentiation and long-term stability in vitro and in vivo. Thus, ACC1 serves as a dual metabolic and epigenetic hub, regulating immune tolerance and inflammation by balancing de novo lipid synthesis and protein acetylation. |
| format | Article |
| id | doaj-art-4ae1915e035a4e6ea6de526a016b7879 |
| institution | DOAJ |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-4ae1915e035a4e6ea6de526a016b78792025-08-20T02:48:03ZengElsevierMolecular Metabolism2212-87782025-04-019410211110.1016/j.molmet.2025.102111ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerancePhilipp Stüve0Gloria J. Godoy1Fernando N. Ferreyra2Florencia Hellriegel3Fatima Boukhallouk4Yu-San Kao5Tushar H. More6Anne-Marie Matthies7Tatiana Akimova8Wolf-Rainer Abraham9Volkhard Kaever10Ingo Schmitz11Karsten Hiller12Matthias Lochner13Benoît L. Salomon14Ulf H. Beier15Michael Rehli16Tim Sparwasser17Luciana Berod18Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Germany; A Joint Venture Between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover 30625, Germany; Leibniz Institute for Immunotherapy, Regensburg, Germany; Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55122, GermanyInstitute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, GermanyInstitute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany; Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina; Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, ArgentinaInstitute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany; Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina; Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, ArgentinaInstitute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55122, GermanyInstitute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55122, GermanyDepartment of Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, 38106 Braunschweig, GermanySystems-Oriented Immunology and Inflammation Research Group, Department of Experimental Immunology, HZI, Braunschweig 38124, Germany; Institute for Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg 39106, Germany; Institute for Molecular Immunology, Ruhr-University Bochum, Bochum 44801, GermanyDivision of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, 38106 Braunschweig, Germany; Department of Chemical Microbiology, HZI, Braunschweig 38124, GermanyResearch Core Unit Metabolomics, MHH, Hannover 30625, GermanySystems-Oriented Immunology and Inflammation Research Group, Department of Experimental Immunology, HZI, Braunschweig 38124, Germany; Institute for Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg 39106, Germany; Institute for Molecular Immunology, Ruhr-University Bochum, Bochum 44801, GermanyDepartment of Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, 38106 Braunschweig, GermanyInstitute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Germany; A Joint Venture Between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover 30625, Germany; Institute of Medical Microbiology and Hospital Epidemiology, MHH, Hannover 30625, GermanySorbonne Université, INSERM, CNRS, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris 75013, FranceDivision of Nephrology and Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USALeibniz Institute for Immunotherapy, Regensburg, Germany; Department of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyInstitute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55122, Germany; Research Center for Immunotherapy (FZI), University Medical Center Mainz, 55131 Mainz, GermanyInstitute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany; Research Center for Immunotherapy (FZI), University Medical Center Mainz, 55131 Mainz, Germany; Corresponding author. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany.Objective: Regulatory T cells (Tregs) are essential in maintaining immune tolerance and controlling inflammation. Treg stability relies on transcriptional and post-translational mechanisms, including histone acetylation at the Foxp3 locus and FoxP3 protein acetylation. Additionally, Tregs depend on specific metabolic programs for differentiation, yet the underlying molecular mechanisms remain elusive. We aimed to investigate the role of acetyl-CoA carboxylase 1 (ACC1) in the differentiation, stability, and function of regulatory T cells (Tregs). Methods: We used either T cell-specific ACC1 knockout mice or ACC1 inhibition via a pharmacological agent to examine the effects on Treg differentiation and stability. The impact of ACC1 inhibition on Treg function was assessed in vivo through adoptive transfer models of Th1/Th17-driven inflammatory diseases. Results: Inhibition or genetic deletion of ACC1 led to an increase in acetyl-CoA availability, promoting enhanced histone and protein acetylation, and sustained FoxP3 transcription even under inflammatory conditions. Mice with T cell-specific ACC1 deletion exhibited an enrichment of double positive RORγt+FoxP3+ cells. Moreover, Tregs treated with an ACC1 inhibitor demonstrated superior long-term stability and an enhanced capacity to suppress Th1/Th17-driven inflammatory diseases in adoptive transfer models. Conclusions: We identified ACC1 as a metabolic checkpoint in Treg biology. Our data demonstrate that ACC1 inhibition promotes Treg differentiation and long-term stability in vitro and in vivo. Thus, ACC1 serves as a dual metabolic and epigenetic hub, regulating immune tolerance and inflammation by balancing de novo lipid synthesis and protein acetylation.http://www.sciencedirect.com/science/article/pii/S2212877825000183ACC1Adoptive Treg transferEpigenetic regulationFatty acid synthesisTreg stabilityAcetylation |
| spellingShingle | Philipp Stüve Gloria J. Godoy Fernando N. Ferreyra Florencia Hellriegel Fatima Boukhallouk Yu-San Kao Tushar H. More Anne-Marie Matthies Tatiana Akimova Wolf-Rainer Abraham Volkhard Kaever Ingo Schmitz Karsten Hiller Matthias Lochner Benoît L. Salomon Ulf H. Beier Michael Rehli Tim Sparwasser Luciana Berod ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance Molecular Metabolism ACC1 Adoptive Treg transfer Epigenetic regulation Fatty acid synthesis Treg stability Acetylation |
| title | ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance |
| title_full | ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance |
| title_fullStr | ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance |
| title_full_unstemmed | ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance |
| title_short | ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance |
| title_sort | acc1 is a dual metabolic epigenetic regulator of treg stability and immune tolerance |
| topic | ACC1 Adoptive Treg transfer Epigenetic regulation Fatty acid synthesis Treg stability Acetylation |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000183 |
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