The development of thymic B cells and their role in T cell negative selection (P5039)

Abstract

Abstract T cell negative selection is dependent on the presentation of self antigens by MHC expressing cells in the thymic medulla. In addition to dendritic cells and medullary thymic epithelial cells, thymic B cells also reside in the medulla and express high levels of MHC class II. The origin of these cells is unclear, with both intrathymic development and recirculation of mature B cells being reported. Using parabiosis studies and analysis of Rag-2-GFP BAC transgenic mice, we found that recirculation contributes minimally while development from thymic progenitors is the predominant pathway that maintains this population. Given their phenotype and high capacity to present cognate antigens, we hypothesized that thymic B cells play a role in T cell negative selection. Using the KRN TCR transgenic that recognizes the self antigen GPI, we tested how negative selection was affected when we altered B cell antigen presentation. When the KRN TCR was crossed to a GPI-specific BCR knockin that increased GPI presentation on B cells, negative selection of the KRN TCR was enhanced. When we eliminated thymic B cells by crossing the KRN TCR onto a μMT-/- background, negative selection was reduced, suggesting that the endogenous B cell repertoire contributes to negative selection of this physiologically relevant antigen. Given the high frequency of autoreactivity in immature B cells, we argue that B cell tolerance and T cell tolerance could be efficiently coupled in T cell negative selection.