Mechanisms of Peripheral Induction of T-Cell Tolerance

T 细胞耐受的外周诱导机制

• 批准号: 8109578
• 负责人: MATTHEW Franklin MESCHER
• 金额: $ 6.3万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109578
• 关键词: Address; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Biological; CD4 Positive T Lymphocytes; Cells; Characteristics; Clinical; Collaborations; Development; Disease; Grant; Immune response; Immune system; Immunity; Immunotherapy; In Vitro; Individual; Lead; Mature T-Lymphocyte; Medicine; Methodology; Modeling; Molecular; Nature; Peptides; Peripheral; Reagent; Renal carcinoma; Research Personnel; Role; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Thymus Gland; Transplantation; Virus; Work; design; in vivo Model; melanoma; novel; peripheral tolerance; programs; response; tumor; tumor immunology

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.

T淋巴细胞必须通过快速增殖和分化对特异性抗原作出反应，以产生有效的免疫应答。关键的是，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中的阴性选择实现的。然而，这并不完全，一些自身反应性T细胞逃逸到外周。存在使这些成熟T细胞耐受的机制，但对它们知之甚少。 该计划正在使用体外和体内模型解决成熟T细胞中这些机制的性质。在项目I（Jenkins）和II（Mueller）中研究了CD4 T细胞的外周耐受性，在项目III（Hogquist）和IV（Mescher）中研究了CDS T细胞的外周耐受性。因此，两种主要的T细胞亚群都被 研究了此外，项目I和III使用新模型在生物水平上检查CD4和CDS T细胞耐受性，项目II和IV在分子水平上检查CD4和CDS T细胞的耐受机制。计划的工作涉及调查人员之间的广泛协作互动。 预计这些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。了解这些机制，从而如何操纵它们，有可能有助于改善移植和疾病治疗。诱导对自身抗原的耐受性的机制也可能诱导对外来抗原的耐受性，包括存在于肿瘤或病毒感染的细胞上的那些抗原，导致免疫系统无法产生保护性应答。最后，使用确定的肽抗原来诱导针对广泛疾病的保护性或治疗性免疫具有巨大潜力，并且目前大量的努力集中在这方面。然而，越来越清楚的是，必须非常谨慎地使用这些药物，因为它们也可能引起耐受性，从而可能导致保护作用减弱或疾病加重。因此，如本计划中所提出的，更好地理解可能导致T细胞耐受的机制，其意义远远超出了自身免疫性疾病。