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B Cells Promote Intra-Islet CD8⁺ Cytotoxic T Lymphocyte Survival To Enhance Type 1 Diabetes

¹Department of Pathology, Cambridge Institute for Medical Research, Cambridge University, Addenbrooke's Hospital, Hills Road, Cambridge. CB2 0XY. UK
²Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
³Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol BS8 1TD, UK

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 monitored. In vitro antigen presentation assays, in vivo administration of the bromodeoxyuridine coupled to flow cytometry assays assessed 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 CTL 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. Re-introduction of B cells incapable of secreting Ig 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 CTL.

Conclusion: In inflamed islets, B cells are central for the efficient intra-islet survival of CTL thereby promoting type 1 diabetes development.

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