Specificity and Function of CD25+ Regulatory T Cells

CD25 调节性 T 细胞的特异性和功能

• 批准号: 6756805
• 负责人: ANDREW J CATON
• 金额: $ 32.37万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6756805
• 关键词: B lymphocyte; T cell receptor; T lymphocyte; antigen presenting cell; autoimmune disorder; autoimmunity; cellular immunity; genetically modified animals; helper T lymphocyte; immune response; immune tolerance /unresponsiveness; immunoregulation; laboratory mouse; lymph nodes; microorganism hemagglutinin; thymus; thymus transplantation

DESCRIPTION (provided by applicant): The goal is to use a well-characterized model system to define processes governing the selection and activity of CD4+ CD25+ regulatory T cells (CD25+ Treg). The application centers on transgenic mice expressing the influenza virus PR8 hemagglutinin (HA) under the control of a variety of promoters, and co-expressing HA specific T cell receptors. Preliminary studies have shown that HA-specific T cells undergo selection to become CD25+ Treg to varying extents in these different lineages, and in some cases overt autoimmune disease (myocarditis, inflammatory arthritis) can develop. The application will determine how specificity for HA peptides directs CD25+ Treg repertoire formation and influences the ability of CD25+ Treg to prevent antigen-specific immune responses in HA Tg mice. Aim 1 will determine how interactions with self-peptides direct CD25+ Treg repertoire formation. How expression of self-peptides in different amounts and/or cell types directs CD25+ Treg selection in the thymus will be examined. In addition, how interactions with self peptides in the periphery contribute to CD25+ Treg repertoire formation will be assessed. Aim 2 will examine how T cell receptor (TCR) specificity directs the selection and function of CD25+ Treg. The specificity with which autoreactive TCRs interact with self-peptides during CD25+ Treg selection will be determined, and the specificity requirements for the activation and effector function of CD25+ Treg will also be defined. Aim 3 will evaluate how variations in the expression of self-peptides contribute to the ability of CD25+ Treg to prevent autoimmunity. Whether CD25+ Treg accumulate selectively in lymph nodes expressing tissue-specific antigens will be determined. How presentation of self-peptides at high levels by antigen presenting cells contributes to the ability of CD25+ Treg to prevent autoimmunity will also be assessed. These studies will provide fundamental insights into the mechanisms of immune tolerance, and into processes that can lead to the development of autoimmune disease. They will increase our understanding of the development and activity of CD25+ Treg, and of their potential application in novel therapeutic approaches for disease treatment.

描述(由申请人提供)：目标是使用一个特征良好的模型系统来定义管理CD4+CD25+调节性T细胞(CD25+Treg)选择和活性的过程。其应用主要集中在在多种启动子的控制下表达流感病毒PR8血凝素(HA)的转基因小鼠，并共表达HA特异性T细胞受体。初步研究表明，在这些不同的谱系中，HA特异的T细胞经过不同程度的选择，成为CD25+Treg，在某些情况下，可以发展为明显的自身免疫性疾病(心肌炎、炎症性关节炎)。这项应用将确定HA多肽的特异性如何指导CD25+Treg谱系的形成，并影响CD25+Treg在HA TG小鼠中预防抗原特异性免疫反应的能力。目标1将确定与自体肽的相互作用如何引导CD25+Treg谱系的形成。不同数量和/或细胞类型的自体肽的表达如何指导胸腺中CD25+Treg的选择将被研究。此外，还将评估与外周自体多肽的相互作用如何有助于CD25+Treg谱系的形成。目的2将研究T细胞受体(TCR)特异性如何指导CD25+Treg的选择和功能。在CD25+Treg选择过程中，自身反应性TCR与自身多肽相互作用的特异性将被确定，CD25+Treg激活和效应功能的特异性要求也将被定义。目的3将评估自体多肽表达的变化如何有助于CD25+Treg预防自身免疫的能力。CD25+Treg是否选择性地积聚在表达组织特异性抗原的淋巴结中将被确定。还将评估抗原提呈细胞高水平递呈自体多肽如何有助于CD25+Treg预防自身免疫的能力。这些研究将为免疫耐受的机制以及可能导致自身免疫性疾病发展的过程提供基本的见解。它们将增加我们对CD25+Treg的发展和活性的理解，以及它们在疾病治疗新疗法中的潜在应用。