Su Zhangyao, Bian Lingling, Zhao Hang, Cai Yun, Yang Tao, Li Shushu, Xu Xinyu
Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Endocrinology, The First People's Hospital of Yancheng, Yancheng, Jiangsu, China.
Front Immunol. 2025 Jul 10;16:1623428. doi: 10.3389/fimmu.2025.1623428. eCollection 2025.
T cells are crucial in destroying pancreatic β cells, resulting in insulitis in type 1 diabetes (T1D). However, only 1% to 2% of infiltrating CD8 T cells are specific for islet autoantigens. The mechanisms driving non-cognate T cells to the islets and their potential pathogenic roles remain unclear.
We analyzed the frequency and function of circulating gut-tropic immune cells in 99 patients with T1D and 57 healthy controls. We also analyzed single-cell RNA sequencing on pancreata from 10 T1D donors, 11 autoantibody-positive donors, and 15 non-diabetic controls. Correlation analysis was performed to elucidate the relationship between gut-tropic cells and clinical variables. In NOD mice, we examined gut-tropic T cell frequencies, cytokine profiles, and cytotoxicity at different disease stages. Additionally, we investigated the role of integrin α4β7 on gut-tropic T cells function and migration.
Gut-tropic CD8 T cells are reduced in peripheral blood but elevated in pancreatic islets of patients with T1D, correlating with impaired β-cell function. Gut-tropic CD8 T cells exhibited stronger cytokine production than non-gut-tropic counterparts. In NOD mice, gut-tropic cells increased in the islets and decreased in the blood during insulitis progression. Gut-tropic CD8 T cells showed augmented cytokine production and cytotoxicity against islet cells. Integrin α4β7 was a key mediator of the pathogenicity of CD8 T cells and upregulated by the inflammatory signals. Insulitis directly drove gut-tropic CD8 T cells migrating to inflamed islets.
Gut-tropic CD8 T cells bridge the intestinal immune system and the pathogenesis of T1D, offering potential biomarkers and therapeutic targets.
T细胞在破坏胰腺β细胞从而导致1型糖尿病（T1D）胰岛炎方面起着关键作用。然而，只有1%至2%浸润的CD8 T细胞对胰岛自身抗原有特异性。驱动非同源T细胞迁移至胰岛的机制及其潜在致病作用仍不清楚。
我们分析了99例T1D患者和57名健康对照者循环中归巢于肠道的免疫细胞的频率和功能。我们还对10例T1D供体、11例自身抗体阳性供体和15例非糖尿病对照者的胰腺进行了单细胞RNA测序。进行相关性分析以阐明归巢于肠道的细胞与临床变量之间的关系。在非肥胖糖尿病（NOD）小鼠中，我们检测了不同疾病阶段归巢于肠道的T细胞频率、细胞因子谱和细胞毒性。此外，我们研究了整合素α4β7在归巢于肠道的T细胞功能和迁移中的作用。
归巢于肠道的CD8 T细胞在T1D患者外周血中减少，但在胰腺胰岛中升高，与β细胞功能受损相关。归巢于肠道的CD8 T细胞比不归巢于肠道的对应细胞表现出更强的细胞因子产生能力。在NOD小鼠中，在胰岛炎进展过程中，归巢于肠道的细胞在胰岛中增加而在血液中减少。归巢于肠道 的CD8 T细胞对胰岛细胞表现出增强的细胞因子产生能力和细胞毒性。整合素α4β7是CD8 T细胞致病性的关键介质，并被炎症信号上调。胰岛炎直接驱使归巢于肠道的CD8 T细胞迁移至炎症胰岛。
归巢于肠道的CD8 T细胞连接肠道免疫系统与T1D的发病机制，提供了潜在的生物标志物和治疗靶点。
