Specificity and Function of CD25+ Regulatory T Cells

描述（由申请人提供）：目标是使用充分表征的模型系统来定义控制CD 4 + CD 25+调节性T细胞（CD 25 + Treg）的选择和活性的过程。该应用集中于在多种启动子控制下表达流感病毒PR 8血凝素（HA）并共表达HA特异性T细胞受体的转基因小鼠。初步研究表明，HA特异性T细胞在这些不同谱系中经历不同程度的选择以成为CD 25 + Treg，并且在某些情况下可以发展明显的自身免疫性疾病（心肌炎，炎性关节炎）。该应用将确定HA肽的特异性如何指导CD 25 + Treg库形成并影响CD 25 + Treg阻止HA Tg小鼠中抗原特异性免疫应答的能力。目的1将确定与自身肽的相互作用如何指导CD 25 + Treg库的形成。将检查不同量和/或细胞类型的自身肽的表达如何指导胸腺中的CD 25 + Treg选择。此外，将评估与外周中的自身肽的相互作用如何促进CD 25 + Treg库形成。目的2将研究T细胞受体（TCR）特异性如何指导CD 25 + Treg的选择和功能。将确定在CD 25 + Treg选择期间自身反应性TCR与自身肽相互作用的特异性，并且还将定义CD 25 + Treg的活化和效应子功能的特异性要求。目的3将评估自身肽表达的变化如何有助于CD 25 + Treg预防自身免疫的能力。将确定CD 25 + Treg是否选择性地在表达组织特异性抗原的淋巴结中积聚。还将评估抗原呈递细胞如何以高水平呈递自身肽有助于CD 25 + Treg预防自身免疫的能力。这些研究将为免疫耐受机制以及可能导致自身免疫性疾病发展的过程提供基本见解。它们将增加我们对CD 25 + Treg的发展和活性的理解，以及它们在疾病治疗的新治疗方法中的潜在应用。

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.