Intrinsic and Extrinsic Controls of B Cell Tolerance

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The immature B cell stage is the first developmental stage where a B cell can recognize and respond to polymorphic antigen, and therefore where endogenous or self-antigens can initially be recognized. As such, the emergence of immature B cells provides the first opportunity to purge the repertoire of self-reactive B cells with the potential to initiate autoimmune disease. We have recently found that the B cell receptor (BCR) on immature B cells fails to compartmentalize into lipid rafts following aggregation and that this is associated with abortive signaling. Based on our cumulative data, we have argued that the intrinsic or "hardwired" response of BCR stimulated immature B cells is apoptotic, suggesting that deletion is the default mechanism for tolerance at this stage. However, it is quite clear that deletion is not the sole mechanism for the elimination of self-reactive immature B cells. We have identified a cellular constituent in the bone marrow (BM) that can protect the BCR-stimulated immature B cell from apoptosis and redirect the response to continued immunoglobulin (Ig) light chain recombination and receptor editing. Finally, our data indicate that antigen-specific T cells can abort BCR-induced apoptosis by peripheral transitional immature B cells and redirect them towards an activation program. The proposed continuation of these studies will focus on defining the mechanisms underlying these processes in vitro as well as to establish their immunological relevance in vivo. Three specific aims are proposed: (1) determine if the intrinsic inability of the BCR to compartmentalize into lipid rafts in immature B cells prevents sustained BCR signaling and if developmentally regulated differences in plasma membrane cholesterol and lipid composition influence BCR-induced signaling; (2) define the cellular identity of the BM protective cell (BMPC), the mechanisms involved in modulating the apoptotic response of antigen-stimulated immature B cells, and its specific role in regulating receptor editing; and, (3) define the ability of transitional immature B cells to elicit anti-apoptotic signals from antigen-specific T cells and assess the impact of this interaction on T cell responses to secondary antigen encounter. Together with other members of this program, these studies will address issues relevant to the induction and maintenance of immune cell tolerance to self-antigens. Importantly, these studies will consider the complex microenvironments in which these processes occur while at the same time addressing these issues at the mechanistic level.