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 由物理消除或在某些情况下产生的过程 自我反应性淋巴细胞的功能性沉默。它已经被欣赏了 在一段时间内，处于不同发育阶段的B细胞显示 对耐受性诱导的分化敏感性；未成熟阶段B为 对抗原的负选择高度敏感，而成熟的B细胞 被激活了。在不成熟和不成熟之间观察到的功能二分法 成熟B细胞对B细胞抗原受体(BCR)结合的反应 提示发育调节的信号特性是 B细胞可以在决定B细胞是否将被 在抗原刺激后被消除或激活。然而，这个想法 B细胞的耐受性完全是由内在调节的 对BCR信号的响应似乎过于简单化，因为它正在变得 越来越清楚的是，B细胞外的过程也是 在这些决策中很重要。同样，外在因素似乎也会影响 影响成熟期B阶段在遭遇以下事件后的最终反应 自身抗原。这里提出的研究的中心前提是 未成熟和成熟B细胞的固有程序可以通过 二次或共刺激信号，改变这些细胞的命运 BCR接洽。我们建议通过体外培养来检验这一假设。 模拟系统来描述这些过程在细胞和 分子水平。与方案项目的中心主题保持一致， 这些研究旨在解决问题的复杂性和可塑性 免疫系统在诱导和维持内源性耐受中的作用 抗原。具体来说，我们将解决以下问题：(1)是否 抗原相遇部位对幼龄期B细胞反应的影响 细胞BCR-交联；(2)外周幼稚B细胞能否挽救 从负面选择中被招募到免疫反应中 抗原反应性T细胞；以及，(3)T细胞的缺失有什么影响 细胞来源的共刺激信号在BCR诱导的增殖物上的作用 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.