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Diabetes. 2019 Feb 22. pii: db180487. doi: 10.2337/db18-0487. [Epub ahead of print]

Altered Gut Microbiota Activate and Expand Insulin B15-23-Reactive CD8+ T-Cells.

Author information

1
Diabetes Research Group, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN, Wales, UK.
2
Section of Endocrinology, School of Medicine, Yale University, New Haven, Connecticut 06519, USA.
3
Diabetes Research Group, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN, Wales, UK wongfs@cardiff.ac.uk.

Abstract

Insulin is a major autoantigen in type 1 diabetes, targeted by both CD8 and CD4 T-cells. We studied an insulin-reactive T-cell receptor (TCR) alpha-chain transgenic non-obese diabetic (NOD) mouse on a TCRCα and proinsulin2 (PI2)-deficient background, designated as A22Cα -/- PI2 -/- NOD mice. These mice develop a low incidence of autoimmune diabetes. To test the role of gut microbiota on diabetes development in this model system, we treated the A22Cα -/- PI2 -/- NOD mice with enrofloxacin, a broad-spectrum antibiotic. The treatment led to male mice developing accelerated diabetes. We found that enrofloxacin increased the frequency of the insulin-reactive CD8+ T-cells and activated the cells in the Peyer's patches (PP) and pancreatic lymph nodes (PLNs), together with induction of immunological effects on the antigen-presenting cell populations. The composition of gut microbiota differed between the enrofloxacin-treated and untreated mice and also between the enrofloxacin-treated mice that developed diabetes, compared with those that remained normoglycemic. Our results provide evidence that the composition of the gut microbiota is important for determining the expansion and activation of insulin-reactive CD8+ T-cells.

PMID:
30796028
DOI:
10.2337/db18-0487

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