Mechanisms of Peripheral Induction of T-Cell Tolerance

描述（由申请人提供）：T淋巴细胞必须通过快速增殖和分化对特定抗原作出反应，以形成有效的免疫反应。重要的是，这只发生在对外来抗原的反应中，这样自身抗原就不会诱导自身免疫反应。对自身抗原的耐受性部分是通过胸腺的负选择实现的。然而，这是不完全的，一些自身反应性T细胞逃逸到外周。使这些成熟T细胞具有耐受性的机制是存在的，但人们对它们知之甚少。该项目利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II （Mueller）正在研究CD4 T细胞的外周耐受性，项目III （Hogquist）和IV （Mescher）正在研究CD8 T细胞的外周耐受性。因此，两种主要的T细胞亚群都在研究中。此外，项目I和III使用新模型在生物学水平上检测CD4和CD8 T细胞的耐受性，项目II和IV在分子水平上检测CD4和CD8 T细胞的耐受性机制。计划中的工作涉及调查者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。了解这些机制，以及如何操纵它们，有可能有助于改善移植和疾病治疗。诱导机制

DESCRIPTION (provided by applicant): 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 CD8 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 CD8 T cell tolerance at the biological level using novel models, and Projects II and IV examine tolerance mechanisms in CD4 and CD8 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. PROJECT 1: Analysis of Peripheral Tolerance in vivo (Jenkins, M.) PROJECT 1 DESCRIPTION (provided by applicant): The long-term goal of this project is an understanding of the mechanisms that account for CD4+ T cell tolerance to antigens that are presented in the secondary lymphoid organs but not the thymus. Previously, we showed that naive CD4+ T cells that are exposed to model antigens in the secondary lymphoid organs in the absence of inflammation proliferate poorly, then most of the progeny die, and the survivors enter an anergic state characterized by poor lymphokine production. The goal of this application is to establish whether or not a similar series of events accounts for peripheral tolerance to certain natural self-proteins. This has become a pressing issue since the discovery that the AIRE transcription factor drives ectopic expression of extrathymic gene products in the thymus. Thus, it remains possible that the physiological role that peripheral tolerance was thought to play is really played by AIRE-mediated intrathymic tolerance. Here, we will test the hypothesis that peripheral tolerance is physiologically-relevant by using new tools to identify the tolerance mechanisms that apply to two pregnancy-specific proteins, one that appears to be regulated by AIRE and another that does not, and one sperm-specific protein. We will determine whether or not these proteins are immunogenic in mice that have never expressed them in the relevant tissue (e.g., non-pregnant female mice), and become non-immunogenic in mice after expression (e.g., pregnant female mice). The relevant antigenic peptides will be identified and used to produce peptide-MHC II multimers. The multimers will then be used with a sensitive new enrichment method capable of detecting fewer than 100 cells per mouse to enumerate peptide MHC II specific CD4+ T cells before, during, and after expression of the relevant protein within the polyclonal repertoires of normal mice. This approach should reveal whether or not the relevant CD4+ T cells are deleted, turn into regulatory cells, or become anergic during or after the period when these developmentally regulated self-proteins are expressed. This approach will then be used in gene-targeted mice to determine whether or not molecules such as Fas and Cbl-b, and others identified by other members of the P01, are involved in the identified tolerance mechanism. Success would provide the first definitive identification of the peripheral tolerance mechanism that applies to a natural self-antigen. This information should help focus future research on the relevant mechanism and shed light on the potential ways that it could fail and lead to autoimmunity.