Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjogren Syndrome-like Inflammation
Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjogren Syndrome-like Inflammation
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DOI：
10.1016/j.celrep.2019.11.010
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发表时间：
2019-12-03
期刊：
影响因子：
8.8
通讯作者：
Chen, Yi-Guang
中科院分区：
文献类型：
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作者：
Ciecko, Ashley E.;Foda, Bardees;Chen, Yi-Guang
人类遗传学研究表明，白细胞介素-27（IL-27）参与了1型糖尿病（T1 D）的发病机制，但其潜在机制仍未得到充分研究。为了进一步确定IL-27在T1 D中的作用，我们产生了IL-27或IL-27 R α缺陷的非肥胖糖尿病（NOD）小鼠。与野生型NOD小鼠相比，NOD.II27（-/-）和NOD.II27ra（-/-）品系都对T1 D完全耐药。来自骨髓细胞的IL-27和T细胞中的IL-27信号传导对于T1 D发展至关重要。IL-27直接改变胰岛中调节性T细胞（Tcl 4）和辅助性T细胞1（Th 1）的平衡，这反过来又调节CD 8 T细胞的致糖尿病活性。IL-27还直接增强胰岛内CD 8 T细胞的效应子功能。除了T1 D，T细胞中的IL-27信号传导也是NOD小鼠中泪腺和唾液腺炎症所需的。我们的研究揭示了IL-27通过多种机制促进NOD小鼠的自身免疫，并为支持其在人类T1 D中的致病作用提供了大量证据。
Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27R alpha. In contrast to wild-type NOD mice, both NOD.II27(-/-) and NOD.II27ra(-/-) strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. IL-27 directly alters the balance of regulatory T cells (Tregs) and T helper 1 (Th1) cells in pancreatic islets, which in turn modulates the diabetogenic activity of CD8 T cells. IL-27 also directly enhances the effector function of CD8 T cells within pancreatic islets. In addition to T1D, IL-27 signaling in T cells is also required for lacrimal and salivary gland inflammation in NOD mice. Our study reveals that IL-27 contributes to autoimmunity in NOD mice through multiple mechanisms and provides substantial evidence to support its pathogenic role in human T1D.