Marginal zone B cells of Non-obese diabetic mice expand with diabetes onset, invade the pancreatic lymph nodes and present auto-antigen to diabetogenic T cells.

Abstract

Objective: B cells are important for disease pathogenesis in the NOD mouse model of type I diabetes. Recent studies demonstrate that marginal zone B cells (MZB), which connect innate with adaptive immune responses, are increased in NOD mice. However, beyond this, the contribution of different B cell subsets to diabetes pathogenesis is poorly understood.

Research Design & Methods: To better understand the role of different B cell subsets in the etiology of type 1 diabetes, we have examined the MZB compartment in NOD mice with respect to their number, distribution and function.

Results: We demonstrate that splenic MZB numbers in female NOD mice undergo a marked ∼3-fold expansion between ∼12-16 weeks of age, co-incident with the onset of frank diabetes. Functionally, NOD MZB are hyper-responsive to TLR9- and CD40-ligation, as well as S1P-dependent chemotactic cues, suggesting an increased sensitivity to selective innate and activation-induced stimuli. Intriguingly, at 16-weeks-of-age, ∼80% of female NOD mice present with MZB-‘like' cells in the PLN. These MZB-‘like' cells express MHC class II, high levels of CD80 and CD86 and their presence in the PLN is associated with an increased frequency of activated Vβ4⁺ CD4⁺ T cells. Significantly, we demonstrate that purified MZB are able to present the auto-antigen insulin to diabetogenic T cells.

Conclusion: These data are consistent with MZB contributing to the pathogenesis of type 1 diabetes as APC's. By integrating innate derived inflammatory signals with the activation of auto-reactive T cells, MZB may help to direct T cell responses against beta cell self-constituents.