Altered chemokine responsiveness has been shown to exclude anergic B cells from splenic follicles, fating them to undergo death by neglect. While this process of """"""""follicular exclusion"""""""" can be mediated by altering expression of the receptor, the rapid changes in migration observed suggest a more immediate mechanism must exist for modulating the response. We have found that chemokine responses are also controlled by regulation of the receptor's intracellular signaling cascade. Specifically, B cell receptor (BCR) stimulation causes inhibition of CXCR4 signaling, mediated by the 5' inositol phosphatase SHIP1. Loss of CXCR4 signaling following BCR engagement results in premature egress of immature B cells from the bone marrow. I propose analysis of the mechanism by which SHIP mediates this inhibition.
Aims will address the mechanism of SHIP targeting to its substrate at remotely stimulated receptors, the role of its catalytic and adapter functions in inhibition, and its dependence on Dok1. These studies investigate a mechanism of negative selection mediated by antigen and chemokine responsiveness, and have relevance to autoimmunity and immunodeficiency, which may result if faulty intracellular signaling impairs this process. ? ? ?
