An interleukin-27-centered cytokine circuit regulates macrophage and T cell interactions in autoimmune diabetes

IF 4.1 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-09-10 DOI:10.1016/j.isci.2025.113537

Ashley E. Ciecko , Rabia Nabi , Amber Drewek , David M. Schauder , Pavel N. Zakharov , Xiaoxiao Wan , Scott M. Lieberman , Weiguo Cui , Martin J. Hessner , Chien-Wei Lin , Yi-Guang Chen

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Abstract

In the non-obese diabetic (NOD) mouse model of autoimmune diabetes, interleukin (IL)-27 stimulates interferon γ (IFNγ) production by CD4 and CD8 T cells and is essential for disease development. Here, we tested the role of IL-27 in cellular communication. Single-cell RNA sequencing and T cell adoptive transfer showed that IL-27 intrinsically controlled the differentiation of islet-infiltrating CD4 T cells by driving them toward an IL-21⁺ Th1 phenotype. Consequently, IL-27 signaling in CD4 T cells was important for BATF and granzyme B expression in islet CD8 T effectors. BATF overexpression increased the diabetogenic potential of β cell autoreactive CD8 T cells lacking help from CD4 T cell-derived IL-21. Macrophages were the main source of IL-27 in the islets, whose expression correlated with T cell infiltration. IFNγ and CD40 signaling conferred by activated T cells induced macrophage IL-27 production. Collectively, our findings reveal a role for IL-27 in orchestrating interconnected positive feedback loops involving CD4 T cells, CD8 T cells, and macrophages in autoimmune diabetes.

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以白细胞介素27为中心的细胞因子回路调节自身免疫性糖尿病中巨噬细胞和T细胞的相互作用

在自身免疫性糖尿病的非肥胖糖尿病（NOD）小鼠模型中，白细胞介素(IL)-27刺激CD4和CD8 T细胞产生干扰素γ (IFNγ)，是疾病发展所必需的。在这里，我们测试了IL-27在细胞通讯中的作用。单细胞RNA测序和T细胞过继转移表明，IL-27通过驱动浸润胰岛的CD4 T细胞向IL-21+ Th1表型发展，内在地控制着它们的分化。因此，CD4 T细胞中的IL-27信号对于胰岛CD8 T效应物中BATF和颗粒酶B的表达是重要的。BATF过表达增加了缺乏CD4 T细胞来源IL-21帮助的β细胞自身反应性CD8 T细胞的致糖尿病潜能。巨噬细胞是胰岛IL-27的主要来源，其表达与T细胞浸润相关。活化T细胞传递的IFNγ和CD40信号诱导巨噬细胞产生IL-27。总的来说，我们的研究结果揭示了IL-27在自身免疫性糖尿病中协调CD4 T细胞、CD8 T细胞和巨噬细胞相互关联的正反馈回路中的作用。

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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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