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

Pearson, J. A., Kakabadse, D., Davies, J., Peng, J., Warden-Smith, J., Cuff, S., Lewis, M., da Rosa, L. C. , Wen, L. and Wong, F. S. (2019) Altered gut microbiota activate and expand insulin B15-23–reactive CD8+ T cells. Diabetes, 68(5), pp. 1002-1013. (doi: 10.2337/db18-0487) (PMID:30796028)

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) α-chain transgenic NOD mouse on a TCRCα and proinsulin 2 (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 and pancreatic lymph nodes, 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.

• Item Type: Articles
• Additional Information: J.A.P. was a recipient of a Diabetes UK PhD studentship and subsequently a Fulbright-Diabetes UK postdoctoral research scholarship. The work was funded by National Institutes of Health grants (DK-092882, DK-100500, and P30-DK-45735) to L.W. and by a European Foundation for the Study of Diabetes grant (NN 2014_6) and Medical Research Council grant (G0901155) to F.S.W.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Camargo da Rosa, Dr Larissa
• Authors: Pearson, J. A., Kakabadse, D., Davies, J., Peng, J., Warden-Smith, J., Cuff, S., Lewis, M., da Rosa, L. C., Wen, L., and Wong, F. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Diabetes
• Publisher: American Diabetes Association
• ISSN: 0012-1797
• ISSN (Online): 1939-327X
• Published Online: 22 February 2019
• Copyright Holders: Copyright © 2019 American Diabetes Association
• First Published: First published in Diabetes 68(5): 1002-1013
• Publisher Policy: Reproduced in accordance with the publisher copyright policy