Specificity and Function of CD25+ Regulatory T Cells

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控制CD4+ CD25+调节性T细胞（CD25+ Treg）的选择和活性的过程。应用于在多种启动子控制下表达流感病毒PR8血凝素（HA）的转基因小鼠，并共同表达HA特异性T细胞受体。初步研究表明，ha特异性T细胞在这些不同的谱系中经历不同程度的选择成为CD25+ Treg，在某些情况下可发展为明显的自身免疫性疾病（心肌炎、炎症性关节炎）。该应用程序将确定HA肽的特异性如何指导CD25+ Treg库的形成，并影响CD25+ Treg阻止HA Tg小鼠抗原特异性免疫反应的能力。目的1将确定与自身肽的相互作用如何直接CD25+ Treg库的形成。在胸腺中，不同数量和/或细胞类型的自身肽的表达如何指导CD25+ Treg的选择将被研究。此外，将评估与外周自身肽的相互作用如何促进CD25+ Treg库的形成。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将评估自身肽表达的变化如何促进CD25+ Treg预防自身免疫的能力。CD25+ Treg是否在表达组织特异性抗原的淋巴结中选择性积累将被确定。抗原呈递细胞高水平呈递自身肽如何促进CD25+ Treg预防自身免疫的能力也将被评估。这些研究将为免疫耐受的机制和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的发育和活性的理解，以及它们在疾病治疗新方法中的潜在应用。

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.