Intrinsic and extrinsic control of B cells tolerance

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DESCRIPTION (provided by applicant): The immature stage is the first at which the B cell can recognize and respond to polymorphic antigen. As such, this stage marks the point at which endogenous or self-antigens can be recognized thereby providing the initial opportunity to purge the repertoire of self-reactive B cells with the potential to initiate autoimmune disease. We have recently found that the BCR on immature B cells fails to compartmentalize into lipid rafts following aggregation and that this is associated with abortive signaling in these cells. We have argued based on our cumulative data, 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 specificities. We have identified a cellular constituent in the bone marrow that can protect the BCR-stimulated B cell from apoptosis and redirect the response to continued Ig light chain recombination and receptor editing. 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) To determine if the intrinsic inability of the BCR to compartmentalize into lipid rafts in immature B cells prevents sustained BCR signaling; (2) To define the mechanisms accounting for developmental-regulated difference in plasma membrane cholesterol in immature and mature B cell subsets and their role in determining BCR compartmentalization and cell fate decisions consequent to BCR aggregation; and (3) To define the cellular identity of the BM protective cell (BMPC), the cellular and biochemical processes that determine its ability to modulate the apoptotic response of antigen-stimulated immature B cells, and its specific role in regulating receptor editing. Together, these studies will address issues relevant to the induction and maintenance of immune cell tolerance to self-antigens and define processes involved in cell fate decisions following BCR signaling at distinct stages of B cell development.