ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-02-08 DOI:10.1016/j.molmet.2025.102111

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

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引用次数: 0

Abstract

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.

Abstract Image

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ACC1是Treg稳定性和免疫耐受的双代谢-表观遗传调节因子。

目的：调节性T细胞（Tregs）在维持免疫耐受和控制炎症中起着至关重要的作用。Treg的稳定性依赖于转录和翻译后机制，包括Foxp3位点组蛋白乙酰化和Foxp3蛋白乙酰化。此外，treg依赖于特定的代谢程序进行分化，但潜在的分子机制仍然难以捉摸。我们旨在研究乙酰辅酶a羧化酶1 （ACC1）在调节性T细胞（Tregs）分化、稳定性和功能中的作用。方法：我们使用T细胞特异性ACC1敲除小鼠或通过药物抑制ACC1来研究对Treg分化和稳定性的影响。通过Th1/ th17驱动炎性疾病的过继转移模型，在体内评估ACC1抑制对Treg功能的影响。结果：抑制或基因缺失ACC1导致乙酰辅酶a可用性增加，促进组蛋白和蛋白质乙酰化，即使在炎症条件下也能维持FoxP3转录。具有T细胞特异性ACC1缺失的小鼠表现出双阳性RORγt+FoxP3+细胞的富集。此外，在过继转移模型中，用ACC1抑制剂治疗的Tregs表现出优越的长期稳定性和增强的抑制Th1/ th17驱动的炎症性疾病的能力。结论：我们发现乙酰辅酶a羧化酶1 （ACC1）是Treg生物学中的代谢检查点。我们的数据表明，ACC1抑制促进Treg分化和体外和体内的长期稳定性。因此，ACC1作为双重代谢和表观遗传枢纽，通过平衡从头脂质合成和蛋白质乙酰化来调节免疫耐受和炎症。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.