MECHANISMS FOR PERIPHERAL INDUCTION OF T CELL TOLERANCE

T淋巴细胞必须通过快速增殖对特定抗原做出反应 和分化，以建立有效的免疫反应。它是 关键是这只发生在对外来抗原的反应中，所以自我 抗原不能诱导自身免疫反应。T细胞对自身的耐受性 抗原是通过在胸腺中进行负选择来消除的 识别自身抗原的克隆。此外，还存在以下机制 使周围成熟的T细胞对抗原具有耐受性。这 该计划正在解决胸腺细胞中这些机制的性质 和成熟的T细胞在分子和细胞水平上使用两者 体外和体内模型。CD4+T细胞的外周耐受性是 正在研究的第一方案和第二方案，否定选择 第三个项目正在研究I类限制性胸腺细胞 CD8+T细胞的外周耐受性正在进行检测 第四个项目。因此，该方案的四个项目审查了两个 主要类型为T细胞、CD4+细胞和CD8+细胞。这个 计划内的工作涉及 每个项目的调查人员。预计这些调查结果 在计划中的研究中获得的结果将有助于更好地 了解如何避免自身免疫。此外, 了解这些机制，并因此有能力操纵 他们有潜力为改善 移植和疾病治疗。诱导的机制 对自身抗原的耐受也可能导致对外来抗原的耐受。 包括存在于肿瘤或病毒感染细胞上的那些，导致 免疫系统未能产生保护性反应。最后， 使用特定的多肽抗原来诱导 对多种疾病的保护性或治疗性免疫 目前的许多努力都集中在这一点上。然而，它正在成为 越来越清楚地表明，必须非常谨慎地使用这些工具，因为它们 也会导致容忍，这可能会导致保护减弱或 加重的疾病。因此，更好地理解 可导致T细胞耐受的机制，如本报告中所建议的 该计划的影响远远超出了自身免疫性疾病。

T lymphocytes must respond to specific antigen by rapid proliferation and differentiation to mount an effective immune response. It is critical that this occur only in response to foreign antigen, so that self antigens do not induce autoimmune responses. T cell tolerance to self antigen is achieved by negative selection in the thymus to eliminate clones that recognize self antigen. In addition, mechanisms exist for rendering mature T cells in the periphery tolerant to antigens. This Program is addressing the nature of these mechanisms in thymocytes and mature T cells at the molecular and cellular levels using both in vitro and in vivo models. Peripheral tolerance in CD4 plus T cells is being studied in the first Project and second Project, negative selection of class I restricted thymocytes is being examined in the third Project and peripheral tolerance of CD8 plus T cells is being examined in the fourth Project. Thus, the four projects of the Program examine two major types of T cells, CD4 plus cells and CD8 plus cells. The planned work involves extensive collaborative interactions among the investigators of each project. It is anticipated that the findings obtained in the planned studies will contribute to a better fundamental understanding of how autoimmunity is avoided. In addition, understand of these mechanisms, and hence the ability to manipulate them, has the potential to contribute to improvements in transplantation and disease therapy. Mechanisms that induce tolerance to self antigens may also induce tolerance to foreign antigens including those present on tumors or virus-infected cells, resulting in the immune system failing to mount a protective response. Finally, there is great potential for using defined peptide antigens to induce protective or therapeutic immunity for a broad range of disease and much current effort is focusing on this. However, it is becoming increasingly clear that these must be used with great caution since they can also induce tolerance which may lead to lessened protection or excaccerbated disease. Thus, developing a better understanding of the mechanisms that can lead to T cell tolerance, as proposed in this Program, has implications well beyond autoimmune diseases.