Growth of human regulatory CD4+ T cells is more tightly controlled than effector T cells due to distinctive molecular programming

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-04-29 DOI:10.1016/j.isci.2025.112553

Alejandro Moro , Aixin Yu , Luis Nivelo , Zhen Gao , Yuguang Ban , Alejandro V. Villarino , Thomas R. Malek

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引用次数: 0

Abstract

Foreign and self-antigens activate CD4⁺ conventional and regulatory T cells (Tregs) to promote immunity and tolerance, respectively. These cell populations, which depend on interleukin-2 (IL-2), are being expanded and engineered in vitro for adoptive cell therapy (ACT) for cancer and autoimmunity. Here, we investigate the molecular pathways underlying the in vitro expansion of human CD4⁺ Teff and Tregs to TCR/CD28/IL-2 signaling over 12-days. Temporal integration of differential chromatin accessibility and gene expression revealed similar responses over the first 6 days. After this time, T effector (Teff) cells showed greater expansion that was associated with more robust gene activation and chromatin opening that supported increased activation of mTORC1-dependent signaling and a more energetic phenotype. Thus, Tregs are programmed temporally for more limited expansion in vitro that may benefit ACT for cancer but may be a drawback for autoimmunity. These findings may reflect a mechanism to finely tune Treg numbers to maintain homeostasis in vivo.

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人类调节性CD4+ T细胞的生长由于其独特的分子编程而比效应T细胞受到更严格的控制

外源抗原和自身抗原分别激活CD4+常规T细胞和调节性T细胞（Tregs）以促进免疫和耐受性。这些依赖于白细胞介素-2 （IL-2）的细胞群正在体外扩增和改造，用于癌症和自身免疫的过继细胞治疗（ACT）。在这里，我们研究了人类CD4+ Teff和Tregs在体外12天内向TCR/CD28/IL-2信号传导的分子途径。差异染色质可及性和基因表达的时间整合在前6天显示出类似的反应。在此之后，T效应（Teff）细胞表现出更大的扩张，这与更强大的基因激活和染色质开放有关，这支持mtorc1依赖性信号的激活增加和更有活力的表型。因此，treg被暂时编程，以便在体外进行更有限的扩增，这可能有利于ACT治疗癌症，但可能是自身免疫的缺点。这些发现可能反映了一种微调Treg数量以维持体内稳态的机制。

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

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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