INTRINSIC AND EXTRINSIC CONTROLS OF B CELL TOLERANCE

诱导和维持对自身抗原的无反应性是一个复杂的过程， 物理消除或在某些情况下产生的过程 自身反应性淋巴细胞的功能沉默。已经认识到 一段时间后，处于不同发育阶段的B细胞显示 对耐受诱导的不同敏感性;未成熟阶段B是 对抗原阴性选择高度敏感，而成熟B细胞 都被激活了在不成熟和不成熟之间观察到的功能二分法 响应于B细胞抗原受体（BCR）接合的成熟B细胞 表明，发育调节信号固有的属性， B细胞可以在决定B细胞是否将 在抗原刺激后消除或活化。然而， B细胞的耐受性完全受内在调节 对BCR信号的反应似乎过于简单，因为它正在成为 越来越清楚的是，B细胞的外部过程也 在这些决定中很重要。同样，外在因素似乎也 影响成熟阶段B的最终响应， 自身抗原这里提出的研究的中心前提是， 未成熟和成熟B细胞的内在程序可以通过以下方式进行修饰 改变这些细胞命运的次级或共刺激信号， BCR参与。我们建议通过体外培养来验证这一假设 模型系统，以表征这些过程在细胞和 分子水平。根据方案项目的中心主题， 这些研究的目的是解决复杂性和可塑性， 免疫系统在诱导和维持内源性免疫耐受中的作用 抗原具体而言，我们将解决以下问题：（1） 抗原接触部位对未成熟期B细胞免疫应答的影响 外周血未成熟B细胞能否被拯救 从阴性选择中被招募到免疫反应中， 抗原反应性T细胞;（3）缺乏T细胞的影响是什么？ 细胞源性共刺激信号对BCR诱导的增殖 成熟B细胞的反应。

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.