Altered gut microbiota activate and expand insulin B15-23-reactive CD8+ T-cells

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Abstract Summary

Background

Gut microbiota may influence the development of autoimmune diabetes in both humans and Non-obese diabetic (NOD) mice. Recent studies have shown IGRP-reactive CD8+ T-cells exhibit enhanced proinflammatory responses to a bacterial peptide mimic compared to IGRP native autoantigen. However, IGRP-reactive CD8+ T-cells in NOD mice require prior insulin autoreactivity. The aim of our study was to investigate the role of the gut microbiota on insulin-reactive CD8+ T-cells.

Methods

We used an insulin-reactive T-cell receptor (TCR) alpha-chain transgenic NOD mouse (utilizing the TCRα chain from the insulin-reactive G9C8 T-cell clone) on a TCRCα-/- and proinsulin2 (PI2)-deficient background, designated as A22Cα-/-PI2-/-NOD mice. The mice were treated with enrofloxacin, a broad-spectrum antibiotic, at different times in early life. We investigated diabetes development, phenotype and function of the immune cells, as well as the composition of gut microbiota in enrofloxacin-treated and untreated mice.

Results

Male mice treated with enrofloxacin after weaning developed accelerated diabetes. We found that these mice had an increased frequency of the insulin-reactive CD8+ T-cells, with altered TCRβ chain usage, particularly in the pancreatic lymph nodes (PLN), mesenteric lymph nodes (MLN) and Peyer's patches (PP). Furthermore, we observed increased activation of these insulin-reactive CD8+ T-cells in the PP and PLNs. We also found induction of immunological effects on the antigen-presenting cell populations in the enrofloxacin-treated mice. Investigation into the composition of gut microbiota identified differences between enrofloxacin-treated and untreated mice and also between enrofloxacin-treated mice that developed diabetes, compared with those that remained normoglycemic. 

Conclusion

Our results provide evidence that the composition of the gut microbiota is important for determining the expansion and activation of specific clonotypes of insulin-reactive CD8+ T-cells.

Submission ID :
IDS52118
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Yale University
Cardiff University
Cardiff University
Yale University
Yale University
Cardiff University

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KEY DATES

Event dates:
Thursday 25 October - Monday 29 October 2018

Abstract submission deadline:
Monday 14 May 2018

Abstract notification:
July 2018

Early registration deadline:
Monday 3 September 2018

Registration deadline:
Monday 15 October 2018

Contact
British Society for Immunology
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