B-cells promote intra-islet CD8+ cytotoxic T-cell survival to enhance type 1 diabetes.
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.
Brodie
Gillian M
GM
Department of Pathology, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Wallberg
Maja
M
Santamaria
Pere
P
Wong
F Susan
FS
Green
E Allison
EA
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000473:pathology*; D002470:Cell Survival; D016207:Cytokines / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D007249:Inflammation; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D008212:Lymphocyte Depletion; D051379:Mice; D016688:Mice, Inbred NOD
D016207:Cytokines