Antigen-specific regulatory T cells eliminate cognate CD4 effector T cells through perforin, granzyme B, and Bim.

IF 7.7 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2026-09-26 DOI:10.1016/j.celrep.2026.118074

Yanyu Ye, Haoyue Zheng, Jiaqi Duan, Lihua Mo, Yun Liao, Yadong Zheng, Liguo Li, Pengyuan Zheng, Haiyang Han, Chenyang Li, Xiaoyu Liu, Pingchang Yang

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引用次数: 0

Abstract

T cells (Tregs) maintain immune tolerance, yet how they selectively eliminate cognate CD4⁺ effector T cells remains unclear. We propose a co-activation-dependent elimination mechanism, conceptually akin to synthetic lethality. Using in vitro co-cultures, we show that simultaneous peptide-MHC II recognition by Tregs and responders is required to trigger apoptosis-a "double-lock" condition. Dual activation induces perforin and granzyme B in Tregs, while responders become susceptible via TCR-driven Bim upregulation. Conditional deletion of Gzmb, Prf1, or Bcl2l11 abrogates killing. In an OVA-driven airway inflammation model, wild-type but not granzyme B-deficient Tregs reduce lung effector T cells and inflammation, with increased cleaved caspase-3 in targets. This effect requires cognate antigen and occurs without Treg conversion. Human assays recapitulate these findings. Our work defines stringent molecular requirements for Treg-mediated cytotoxicity, informing therapeutic strategies for allergy, autoimmunity, and cancer.

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抗原特异性调节性T细胞通过穿孔蛋白、颗粒酶B和Bim消除同源CD4效应T细胞。

T细胞（Tregs）维持免疫耐受，但它们如何选择性地消除同源CD4+效应T细胞仍不清楚。我们提出一种依赖于共激活的消除机制，在概念上类似于合成致死性。通过体外共培养，我们发现treg和应答者同时识别mhc II肽是触发细胞凋亡的必要条件，这是一种“双锁”条件。双重激活诱导treg中的穿孔素和颗粒酶B，而应答者通过tcr驱动的Bim上调变得易感。有条件地删除Gzmb、Prf1或bcl2111将取消杀戮。在ova驱动的气道炎症模型中，野生型而非颗粒酶b缺陷Tregs减少肺效应T细胞和炎症，靶标中劈裂caspase-3增加。这种作用需要同源抗原，不需要Treg转化。人体试验总结了这些发现。我们的工作定义了treg介导的细胞毒性的严格分子要求，为过敏、自身免疫和癌症的治疗策略提供了信息。

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

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

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. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.