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整合应激反应途径控制组织驻留记忆性CD4 T细胞中的细胞因子产生。

The integrated stress response pathway controls cytokine production in tissue-resident memory CD4 T cells.

作者信息

Asada Nariaki, Ginsberg Pauline, Paust Hans-Joachim, Song Ning, Riedel Jan-Hendrik, Turner Jan-Eric, Peters Anett, Kaffke Anna, Engesser Jonas, Wang Huiying, Zhao Yu, Khatri Robin, Gild Philipp, Dahlem Roland, Diercks Björn-Philipp, Das Sarada, Ignatova Zoya, Huber Tobias B, Prinz Immo, Gagliani Nicola, Mittrücker Hans-Willi, Krebs Christian F, Panzer Ulf

机构信息

III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

出版信息

Nat Immunol. 2025 Apr;26(4):557-566. doi: 10.1038/s41590-025-02105-x. Epub 2025 Mar 6.

DOI:10.1038/s41590-025-02105-x
PMID:40050432
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11957990/
Abstract

Tissue-resident memory T (T) cells are a specialized T cell population that reside in tissues and provide a rapid protective response upon activation. Here, we showed that human and mouse CD4 T cells existed in a poised state and stored messenger RNAs encoding proinflammatory cytokines without protein production. At steady state, cytokine mRNA translation in T cells was suppressed by the integrated stress response (ISR) pathway. Upon activation, the central ISR regulator, eIF2α, was dephosphorylated and stored cytokine mRNA was translated for immediate cytokine production. Genetic or pharmacological activation of the ISR-eIF2α pathway reduced cytokine production and ameliorated autoimmune kidney disease in mice. Consistent with these results, the ISR pathway in CD4 T cells was downregulated in patients with immune-mediated diseases of the kidney and the intestine compared to healthy controls. Our results indicated that stored cytokine mRNA and translational regulation in CD4 T cells facilitate rapid cytokine production during local immune response.

摘要

组织驻留记忆T（T）细胞是一类特殊的T细胞群体，它们驻留在组织中，并在激活后提供快速的保护性反应。在此，我们表明人和小鼠的CD4 T细胞处于一种预激活状态，储存着编码促炎细胞因子的信使核糖核酸（mRNA），但不产生蛋白质。在稳态下，T细胞中的细胞因子mRNA翻译受到综合应激反应（ISR）途径的抑制。激活后，ISR的核心调节因子eIF2α去磷酸化，储存的细胞因子mRNA被翻译以立即产生细胞因子。ISR-eIF2α途径的基因或药理学激活减少了细胞因子的产生，并改善了小鼠的自身免疫性肾病。与这些结果一致，与健康对照相比，在患有肾脏和肠道免疫介导疾病的患者中，CD4 T细胞中的ISR途径被下调。我们的结果表明，CD4 T细胞中储存的细胞因子mRNA和翻译调控有助于在局部免疫反应期间快速产生细胞因子。

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