Mechanisms for 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做出反应，才能产生有效的免疫反应。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。T细胞对自身抗原的耐受性部分是通过胸腺中的负选择来消除识别自身抗原的克隆而实现的。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细胞对自身抗原耐受的机制，但人们对它们知之甚少。该计划正在利用体外和体内模型，在分子和细胞水平上解决成熟T细胞中这些机制的本质。预计在计划研究中获得的结果将有助于更好地从根本上理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广泛疾病的保护性或治疗性免疫具有巨大的潜力，目前的许多努力都集中在这一点上。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 antigens 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 in part by negative selection in the thymus to eliminate clones that recognize self-antigen. This is not complete, however, and some self-reactive T cells escape into the periphery. Mechanisms exist for rendering these mature T cells tolerant to self antigens, but they are poorly understood. This Program is addressing the nature of these mechanisms in mature T cells at the molecular and cellular levels using both in vitro and in vivo models. 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, understanding 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 diseases 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 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.