B Cell Dependent Control of Allograft Tolerance Through Expansion of Thymic CD4+ Foxp3+ T Cells.

Abstract

Introduction: B cells are known to function as producers of antibodies and act as antigen presenting cells, whereas emerging data indicates a role for B cells in transplant tolerance. And although B cells have been reported in the thymus their thymic role is unclear. We have shown that BAFF over-expression can directly control allograft rejection via a peripheral expansion of Tregs. This expansion was shown to be B cell dependent. Results: In new experiments BAFF did not enhance peripheral Treg survival, proliferation or conversion but promoted a ˜3-fold increase in thymic Helios+Treg numbers. Interestingly BAFF also enhanced thymic B cells. Thymic Treg expansion was lost in BAFF-Tg/μMT-/-BM chimeras and B cell null μMT-/-mice exhibited decreased numbers of thymic Tregs. Allograft survival and expansion of thymic Tregs directly correlated to the amount of thymic B cells present resulting in ˜80% islet allograft acceptance. CD19+B cells accumulated in the thymic medulla region close to medullary thymic epithelial cells suggesting a role in thymic Treg selection. Further to this thymic B cells were observed in close proximity to Foxp3+ T cells. In the absence of B cell surface MHC class II, thymic Treg expansion did not occur, indicating the possibility of direct B-Treg interactions in the thymus. Also, thymic Treg expansion did not occur in BAFF-Tg/IgHEL BCRBM chimeras demonstrating a requirement for antigen-specificity. Conclusion: We identify a new role for thymic B cells and present a model whereby intra-thymic B cells provide a source of cognate signals to modulate thymic Treg production. These data demostrate a direct relationship between thymic B cells, thymic Tregs and allograft tolerance.