Mechanisms of Peripheral Induction of T-Cell Tolerance

T淋巴细胞必须通过快速增殖和分化对特定抗原产生反应，才能产生有效的免疫应答。关键的一点是，这只发生在对外来抗原的反应中，这样自身抗原就不会引发自身免疫反应。对自身抗原的耐受性部分是通过胸腺中的负选择来实现的。然而，这并不完全，一些具有自我反应性的T细胞逃逸到外围。存在使这些成熟T细胞耐受的机制，但人们对它们知之甚少。 该计划正在使用体外和体内模型研究成熟T细胞中这些机制的性质。项目I(Jenkins)和项目II(Mueller)以及项目III(Hogquist)和项目IV(Mescher)正在研究CDS T细胞的外周耐受性。因此，T细胞的两个主要亚群都是 学习。此外，项目I和III使用新的模型在生物水平上检查CD4和CDS T细胞的耐受性，项目II和IV在分子水平上检查CD 4和CDS T细胞的耐受机制。计划中的工作涉及调查人员之间广泛的协作互动。 预计在这些研究中获得的发现将有助于更好地理解如何避免自身免疫。对这些机制的了解，以及如何操纵它们，有可能有助于改进移植和疾病治疗。诱导对自身抗原耐受的机制也可能诱导对外来抗原的耐受，包括存在于肿瘤或病毒感染细胞上的抗原，导致免疫系统无法产生保护性反应。最后，使用确定的多肽抗原来诱导对多种疾病的保护性或治疗性免疫具有巨大的潜力，目前的大量工作都集中在这一点上。然而，越来越清楚的是，必须非常谨慎地使用这些药物，因为它们也可能导致耐受性，从而可能导致保护减弱或疾病恶化。因此，更好地了解导致T细胞耐受的机制，正如本计划所建议的那样，其意义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. Tolerance to self-antigen is achieved in part by negative selection in the thymus. This is not complete, however, and some self-reactive T cells escape into the periphery. Mechanisms exist for rendering these mature T cells tolerant, but they are poorly understood. This Program is addressing the nature of these mechanisms in mature T cells using both in vitro and in vivo models. Peripheral tolerance in CD4 T cells is being studied in Projects I (Jenkins) and II (Mueller), and in CDS T cells in Projects III (Hogquist) and IV (Mescher). Thus, both major subsets of T cells are being studied. In addition, Projects I and III examine CD4 and CDS T cell tolerance at the biological level using novel models, and Projects II and IV examine tolerance mechanisms in CD4 and CDS T cells at the molecular levels. The planned work involves extensive collaborative interactions among the investigators. It is anticipated that the findings obtained in these studies will contribute to a better understanding of how autoimmunity is avoided. Understanding of these mechanisms, and hence how 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 diseases and a great deal of 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 that may lead to lessened protection or exacerbated 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.