ORIGINAL RESEARCH article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1623428
This article is part of the Research TopicLymphocytes and Autoimmune Disease: from molecular mechanism to clinical implicationsView all 12 articles
Gut-tropic α4β7 + CD8 + T cells contribute to pancreatic β cell destruction in type 1 diabetes
Provisionally accepted
- 1First Affiliated Hospital, Nanjing Medical University, Nanjing, China
- 2Department of Pediatrics, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing, China
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Background: 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.Results: 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.Conclusions: Gut-tropic CD8⁺ T cells bridge the intestinal immune system and the pathogenesis of T1D, offering potential biomarkers and therapeutic targets.
Keywords: gut tropic T cells, islet function, Integrin α4β7, Autoimmunity, type 1 diabetes
Received: 06 May 2025; Accepted: 25 Jun 2025.
Copyright: © 2025 Su, Bian, Zhao, Cai, Yang, Li and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xinyu Xu, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
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