Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes

Chiara Sorini, Ilaria Cosorich, Marta Lo Conte, Lorena De Giorgi, Federica Facciotti, Roberta Lucianò, Martina Rocchi, Roberto Ferrarese, Francesca Sanvito, Filippo Canducci, Marika Falcone

Research output: Contribution to journalArticle

Abstract

Low-grade intestinal inflammation and alterations of gut barrier integrity are found in patients affected by extraintestinal autoimmune diseases such as type 1 diabetes (T1D), but a direct causal link between enteropathy and triggering of autoimmunity is yet to be established. Here, we found that onset of autoimmunity in preclinical models of T1D is associated with alterations of the mucus layer structure and loss of gut barrier integrity. Importantly, we showed that breakage of the gut barrier integrity in BDC2.5XNOD mice carrying a transgenic T cell receptor (TCR) specific for a beta cell autoantigen leads to activation of islet-reactive T cells within the gut mucosa and onset of T1D. The intestinal activation of islet-reactive T cells requires the presence of gut microbiota and is abolished when mice are depleted of endogenous commensal microbiota by antibiotic treatment. Our results indicate that loss of gut barrier continuity can lead to activation of islet-specific T cells within the intestinal mucosa and to autoimmune diabetes and provide a strong rationale to design innovative therapeutic interventions in “at-risk” individuals aimed at restoring gut barrier integrity to prevent T1D occurrence.

Original languageEnglish
Pages (from-to)15140-15149
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number30
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Autoimmune diabetes
  • Gut inflammation
  • Microbiota

ASJC Scopus subject areas

  • General

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