Activation-induced cytidine deaminase deficiency accelerates autoimmune diabetes in NOD mice

B cells play an important role in type 1 diabetes (T1D) development. However, the role of B cell activation-induced cytidine deaminase (AID) in diabetes development is not clear. We hypothesized that AID is important in the immunopathogenesis of T1D. To test this hypothesis, we generated AID-deficient (AID(-/-)) NOD mice. We found that AID(-/-) NOD mice developed accelerated T1D, with worse insulitis and high levels of anti-insulin autoantibody in the circulation. Interestingly, neither maternal IgG transferred through placenta, nor IgA transferred through milk affected the accelerated diabetes development. AID(-/-) NOD mice showed increased activation and proliferation of B and T cells. We found enhanced T-B cell interactions in AID(-/-) NOD mice, with increased T-bet and IFN-gamma. expression in CD4+T cells in the presence of AID(-/-) B cells. Moreover, excessive lymphoid expansion was observed in AID(-/-) NOD mice. Importantly, antigen-specific BDC2.5 CD4(+) T cells caused more rapid onset of diabetes when cotransferred with AID(-/-) B cells than when cotransferred with AID(+/+) B cells. Thus, our study provides insights into the role of AID in T1D. Our data also suggest that AID is a negative regulator of immune tolerance and ablation of AID can lead to exacerbated islet autoimmunity and accelerated T1D development.