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Marginal-Zone B-Cells of Nonobese Diabetic Mice Expand With Diabetes Onset, Invade the Pancreatic Lymph Nodes, and Present Autoantigen to Diabetogenic T-Cells

From the Immunology and Inflammation Program, Garvan Institute of Medical Research, New South Wales, Australia

Address correspondence and reprint requests to Shane T. Grey, PhD, Senior Research Fellow, Gene Therapy and Autoimmunity Group, Arthritis and Inflammation Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, N5W 2010, Australia. E-mail: s.grey{at}garvan.org.au

Abbreviations: APC, antigen-presenting cell; BAFF, B-cell activator from the tumor necrosis factor family; BrdU, 5-bromo-2-deoxyuridine; FACS, fluorescence-activated cell sorter; FoB, follicular B-cell; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; ILN, inguinal lymph node; MHC, major histocompatibility complex; MLN, mesenteric lymph node; MZB, marginal-zone B-cell; NF, nuclear factor; PLN, pancreatic lymph node; S1P, sphingosine-1-phosphate; TLR, toll-like receptor

OBJECTIVE—B-cells are important for disease pathogenesis in the nonobese diabetic (NOD) mouse model of type 1 diabetes. Recent studies demonstrate that marginal-zone B-cells (MZBs), 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 AND 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, approximately threefold expansion between 12 and 16 weeks of age, coincident with the onset of frank diabetes. Functionally, NOD MZBs are hyperresponsive to toll-like receptor 9 ligation and CD40 ligation, as well as sphingosine-1-phosphate–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 pancreatic lymph node (PLN). These MZB-like cells express major histocompatibility complex class II and 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 MZBs are able to present the autoantigen insulin to diabetogenic T-cells.

CONCLUSIONS—These data are consistent with MZBs contributing to the pathogenesis of type 1 diabetes as antigen-presenting cells. By integrating innate-derived inflammatory signals with the activation of autoreactive T-cells, MZBs may help to direct T-cell responses against β-cell self-constituents.

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