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调节性 T 细胞需要 Sin3a 来稳定表达 Foxp3。

T-regulatory cells require Sin3a for stable expression of Foxp3.

机构信息

Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States.

出版信息

Front Immunol. 2024 Aug 2;15:1444937. doi: 10.3389/fimmu.2024.1444937. eCollection 2024.

DOI:10.3389/fimmu.2024.1444937
PMID:39156895
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11327135/
Abstract

Histone deacetylases 1 and 2 play a major role in the transcriptional regulation of T-regulatory (Treg) cells via interactions with a myriad of coregulatory factors. Sin3a has been well established as a Hdac1/2 cofactor, while its role within Tregs has not been established. In this study, the effects of conditional deletion of Sin3a within Foxp3+ Tregs were evaluated. Developmental deletion of Sin3a from Foxp3+ Tregs resulted in the rapid onset of fatal autoimmunity. Treg numbers were greatly reduced, while residual Tregs had impaired suppressive function. Mice also showed effector T-cell activation, autoantibody production, and widespread tissue injury. Mechanistically, Sin3a deletion resulted in decreased transcription of with a complete lack of CNS2 CpG demethylation. In addition, Foxp3 protein stability was impaired with an increased ex-Treg population. Thus, Sin3a plays a critical role in the maintenance of Treg identity and function and is essential for the expression and stability of Foxp3.

摘要

组蛋白去乙酰化酶 1 和 2 通过与众多共调节因子相互作用，在调节 T 调节（Treg）细胞的转录中发挥主要作用。Sin3a 已被很好地确立为 Hdac1/2 共因子，但其在 Tregs 中的作用尚未确定。在这项研究中，评估了条件性删除 Sin3a 在 Foxp3+Treg 中的作用。从 Foxp3+Treg 中发育性删除 Sin3a 会导致致命自身免疫的快速发作。Treg 数量大大减少，而残留的 Treg 抑制功能受损。小鼠还表现出效应 T 细胞激活、自身抗体产生和广泛的组织损伤。从机制上讲，Sin3a 的缺失导致转录减少，而 CNS2 CpG 去甲基化完全缺失。此外，Foxp3 蛋白稳定性受损，外 Treg 群体增加。因此，Sin3a 在维持 Treg 特性和功能方面发挥着关键作用，是 Foxp3 的表达和稳定性所必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/3936e64f37fb/fimmu-15-1444937-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/8452b07a6f2d/fimmu-15-1444937-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/6f0071e6af62/fimmu-15-1444937-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/d00f2971638e/fimmu-15-1444937-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/45d32ebae3ac/fimmu-15-1444937-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/7475a611a04b/fimmu-15-1444937-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/572159930a19/fimmu-15-1444937-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/d63caebe5263/fimmu-15-1444937-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/3936e64f37fb/fimmu-15-1444937-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/8452b07a6f2d/fimmu-15-1444937-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/6f0071e6af62/fimmu-15-1444937-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/d00f2971638e/fimmu-15-1444937-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/45d32ebae3ac/fimmu-15-1444937-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/7475a611a04b/fimmu-15-1444937-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/572159930a19/fimmu-15-1444937-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/d63caebe5263/fimmu-15-1444937-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16dc/11327135/3936e64f37fb/fimmu-15-1444937-g008.jpg

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本文引用的文献

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Deciphering the TET3 interactome in primary thymic developing T cells.解析原发性胸腺发育中T细胞的TET3相互作用组。
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Tet2 regulates Sin3a recruitment at active enhancers in embryonic stem cells.Tet2在胚胎干细胞的活性增强子处调控Sin3a的募集。
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Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin.
组蛋白 H3 赖氨酸 27 琥珀酰化介导染色质中基因转录抑制。
Mol Cell. 2023 Jul 6;83(13):2206-2221.e11. doi: 10.1016/j.molcel.2023.05.022. Epub 2023 Jun 12.
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The transcriptional regulator Sin3A balances IL-17A and Foxp3 expression in primary CD4 T cells.转录调控因子 Sin3A 平衡初始 CD4 T 细胞中 IL-17A 和 Foxp3 的表达。
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