{"title":"过度激活 EZH2 以提高调节性 T 细胞中的 H3K27me3 水平,可通过驱动早期效应分化增强免疫抑制作用","authors":"Janneke G.C. Peeters, Stephanie Silveria, Merve Ozdemir, Srinivas Ramachandran, Michel DuPage","doi":"10.1016/j.celrep.2024.114724","DOIUrl":null,"url":null,"abstract":"<p>The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and <em>Ezh2</em> deletion in Treg cells causes autoimmunity. Here, we assess whether increasing H3K27me3 levels, by using an <em>Ezh2</em><sup><em>Y641F</em></sup> gain-of-function mutation, will improve Treg cell function. We find that Treg cells expressing <em>Ezh2</em><sup><em>Y641F</em></sup> display an effector Treg phenotype, are poised for improved homing to organ tissues, and can accelerate remission from autoimmunity. The H3K27me3 landscape and transcriptome of naive <em>Ezh2</em><sup><em>Y641F</em></sup> Treg cells exhibit a redistribution of H3K27me3 modifications that recapitulates the gene expression profile of activated <em>Ezh2</em><sup><em>WT</em></sup> Treg cells after CD28 co-stimulation. Altogether, increased H3K27me3 levels promote the differentiation of effector Treg cells that can better suppress autoimmunity.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5000,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hyperactivating EZH2 to augment H3K27me3 levels in regulatory T cells enhances immune suppression by driving early effector differentiation\",\"authors\":\"Janneke G.C. Peeters, Stephanie Silveria, Merve Ozdemir, Srinivas Ramachandran, Michel DuPage\",\"doi\":\"10.1016/j.celrep.2024.114724\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and <em>Ezh2</em> deletion in Treg cells causes autoimmunity. Here, we assess whether increasing H3K27me3 levels, by using an <em>Ezh2</em><sup><em>Y641F</em></sup> gain-of-function mutation, will improve Treg cell function. We find that Treg cells expressing <em>Ezh2</em><sup><em>Y641F</em></sup> display an effector Treg phenotype, are poised for improved homing to organ tissues, and can accelerate remission from autoimmunity. The H3K27me3 landscape and transcriptome of naive <em>Ezh2</em><sup><em>Y641F</em></sup> Treg cells exhibit a redistribution of H3K27me3 modifications that recapitulates the gene expression profile of activated <em>Ezh2</em><sup><em>WT</em></sup> Treg cells after CD28 co-stimulation. Altogether, increased H3K27me3 levels promote the differentiation of effector Treg cells that can better suppress autoimmunity.</p>\",\"PeriodicalId\":9798,\"journal\":{\"name\":\"Cell reports\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.5000,\"publicationDate\":\"2024-09-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell reports\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.celrep.2024.114724\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2024.114724","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Hyperactivating EZH2 to augment H3K27me3 levels in regulatory T cells enhances immune suppression by driving early effector differentiation
The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and Ezh2 deletion in Treg cells causes autoimmunity. Here, we assess whether increasing H3K27me3 levels, by using an Ezh2Y641F gain-of-function mutation, will improve Treg cell function. We find that Treg cells expressing Ezh2Y641F display an effector Treg phenotype, are poised for improved homing to organ tissues, and can accelerate remission from autoimmunity. The H3K27me3 landscape and transcriptome of naive Ezh2Y641F Treg cells exhibit a redistribution of H3K27me3 modifications that recapitulates the gene expression profile of activated Ezh2WT Treg cells after CD28 co-stimulation. Altogether, increased H3K27me3 levels promote the differentiation of effector Treg cells that can better suppress autoimmunity.
期刊介绍:
Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted.
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