CXCR3 expression on antigen-experienced B cells is systemically dysregulated in type 1 diabetes

TL;DR

This study shows that B cells in people with type 1 diabetes have abnormal levels of a molecule called CXCR3, which may affect immune cell movement and disease progression.

Contribution

The study reveals novel dysregulation of CXCR3 expression on antigen-experienced B cells during type 1 diabetes progression.

Findings

CXCR3 expression is reduced on antigen-experienced B cells in long-duration type 1 diabetes.

Recently diagnosed individuals show increased CXCR3 expression on B cells after IFNγ treatment.

CXCR3+CD20+CD8+ T cells are present in the pancreas of recent-onset type 1 diabetes donors.

Abstract

The chemokine receptor C-X-C chemokine receptor type 3 (CXCR3) is a key chemoattractant molecule that facilitates the migration of activated T cells to the pancreas, leading to beta cell death. In this study, we investigated CXCR3 responses in B cells during type 1 diabetes progression.

Peripheral blood samples were obtained from individuals with recent-onset and long-duration type 1 diabetes, who were age- and sex-matched to non-diabetic donors. We isolated peripheral blood mononuclear cells (PBMCs) and examined changes in CXCR3 expression on lymphocytes from donors, performing multiparameter flow cytometry and functional cell culture assays. Human post-mortem pancreatic tissue was obtained from the Exeter Archival Diabetes Biobank. Immunofluorescence staining was used to assess CXCR3 expression in pancreatic tissues.

We observed reduced CXCR3 expression on antigen-experienced B cells in individuals with a long duration of type 1 diabetes, although B cells remained responsive to IFNγ. In individuals who were recently diagnosed, IFNγ treatment resulted in increased CXCR3 expression compared with B cells from non-diabetic donors. B cells in pancreases that were recovered post-mortem from young recent-onset donors lacked CXCR3 expression, but co-staining to detect CD8+ T cells revealed a CXCR3+CD20+CD8+ T cell population, with their circulating counterpart showing increased CXCR3 expression.

We conclude that the CXCR3 response in antigen-experienced B cells is dysregulated during the progression of type 1 diabetes. CXCR3 expression is limited in CD20+ B cells in pancreases from recent-onset individuals diagnosed with type 1 diabetes under 7 years of age, but evident on CD8+ T cells that express CD20.

The online version of this article (10.1007/s00125-025-06608-y) contains peer-reviewed but unedited supplementary material.

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