B-cells promote intra-islet CD8+ cytotoxic T-cell survival to enhance type 1 diabetes

Brodie, Gillian M., Wallberg, Maja, Santamaria, Pere, Wong, Florence Susan ORCID: https://orcid.org/0000-0002-2812-8845 and Green, E. Allison 2008. B-cells promote intra-islet CD8+ cytotoxic T-cell survival to enhance type 1 diabetes. Diabetes 57 (4) , pp. 909-917. 10.2337/db07-1256

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Abstract

OBJECTIVE: To determine the role of B-cells in promoting CD8(+) T-cell-mediated beta cell destruction in chronically inflamed islets. RESEARCH DESIGN AND METHODS-RIP: TNFalpha-NOD mice were crossed to B-cell-deficient NOD mice, and diabetes development was monitored. We used in vitro antigen presentation assays and in vivo administration of bromodeoxyuridine coupled to flow cytometry assays to assess intra-islet T-cell activation in the absence or presence of B-cells. CD4(+)Foxp3(+) activity in the absence or presence of B-cells was tested using in vivo depletion techniques. Cytokine production and apoptosis assays determined the capacity of CD8(+) T-cells transform to cytotoxic T-lymphocytes (CTLs) and survive within inflamed islets in the absence or presence of B-cells. RESULTS: B-cell deficiency significantly delayed diabetes development in chronically inflamed islets. Reintroduction of B-cells incapable of secreting immunoglobulin restored diabetes development. Both CD4(+) and CD8(+) T-cell activation was unimpaired by B-cell deficiency, and delayed disease was not due to CD4(+)Foxp3(+) T-cell suppression of T-cell responses. Instead, at the CTL transition stage, B-cell deficiency resulted in apoptosis of intra-islet CTLs. CONCLUSIONS: In inflamed islets, B-cells are central for the efficient intra-islet survival of CTLs, thereby promoting type 1 diabetes development.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	BrdU, bromodeoxyuridine CTL, cytotoxic T-lymphocyte DC, dendritic cell FACS, fluorescence-activated cell sorter IFN, interferon PLN, pancreatic lymph node RIP, rat insulin promoter TNF, tumor necrosis factor Treg, T regulatory
Publisher:	American Diabetes Association
ISSN:	0012-1797
Last Modified:	18 Oct 2022 14:23
URI:	https://orca.cardiff.ac.uk/id/eprint/17309

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