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B-Cells Promote Intra-Islet CD8⁺ Cytotoxic T-Cell Survival to Enhance Type 1 Diabetes

¹ Department of Pathology, Cambridge Institute for Medical Research, Cambridge University, Addenbrooke's Hospital, Cambridge, U.K
² Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
³ Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol, U.K

Address correspondence and reprint requests to Dr. E.A. Green, Department of Pathology, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K. E-mail: allison.green{at}cimr.cam.ac.uk

Key Words: 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

OBJECTIVE—To determine the role of B-cells in promoting CD8⁺ T-cell—mediated β cell destruction in chronically inflamed islets.

RESEARCH DESIGN AND METHODS—RIP-TNF-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.

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