Inducing and maintaining unresponsiveness to self antigens is a complex process resulting from the physical elimination or in some cases functional silencing of self-reactive lymphocytes. It has been appreciated for some time that B cells at distinct developmental stages display differential sensitivities to tolerance induction; immature-stage B are highly sensitive to negative selection by antigen whereas mature B cells are activated. The functional dichotomy observed between immature and mature B cells in response to B cell antigen receptor (BCR) engagement suggests that developmentally regulated signaling properties intrinsic to the B cell may play pivotal roles in dictating whether a B cell will be eliminated or activated following antigenic stimulation. However, the idea that B cell tolerance is solely governed by intrinsically regulated responses to BCR signaling appears too simplistic, as it is becoming increasingly clear that processes extrinsic to the B cell are also important in these decision. Similarly, extrinsic factors also appear to influence the ultimate response of mature-stage B following encounter with self-antigens. The central premise of the studies proposed here is that the intrinsic program of the immature and mature B cell can be modified by secondary or co-stimulatory signals that alter the fate of these cells to BCR engagement. We propose to test this hypothesis by developing in vitro model systems to characterize these processes at the cellular and molecular level. In keeping with the central theme of the Program Project, these studies are designed to address the complexity and plasticity of the immune system in inducing and maintaining tolerance to endogenous antigens. Specifically, we will address the following questions: (1) does the site of antigen encounter influence the response of immature-stage B cells to BCR-crosslinking; (2) can peripheral immature B cells be rescued from negative selection and be recruited into an immune response by antigen-reactive T cells; and, (3) what is the effect of the absence of T cell-derived co-stimulatory signals on a BCR-induced proliferative response by mature B cells.
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