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: 7213400
• 负责人: ANDREW J CATON
• 金额: $ 34.66万
• 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/7213400
• 关键词: Address; Adoptive Transfer; Affect; Affinity; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Biological Models; CD4 Positive T Lymphocytes; Cardiac; Development; Disease; Goals; Heart; Hemagglutinin; IL2RA gene; Immune Tolerance; Immune response; Lead; Mus; Myocarditis; Numbers; Organ; Pathologic; Peptides; Process; Rheumatoid Arthritis; Specificity; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Lymphocyte; Thymus Gland; Tissues; Transgenic Mice; Transgenic Organisms; Transplantation; Variant; cell type; in vivo; influenzavirus; insight; lymph nodes; novel therapeutics; prevent; promoter; thymocyte

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）：目标是使用良好的模型系统来定义管理CD4+ CD25+调节T细胞（CD25+ Treg）的选择和活动的过程。该应用集中于表达流感病毒PR8血凝素（HA）的转基因小鼠，并在多种启动子的控制下以及共表达的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特异性T细胞经过选择成为CD25+ Treg，以变化量，在某些情况下可以发展出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CD25+ Treg库形成，并影响CD25+ Treg防止HA TG小鼠中抗原特异性免疫反应的能力。 AIM 1将确定与自肽的相互作用如何直接CD25+ Treg库形成。将如何检查在不同量和/或细胞类型中的自肽的表达如何指导胸腺中的CD25+ Treg选择。此外，将评估与周围中自肽的相互作用如何促进CD25+ Treg库形成。 AIM 2将检查T细胞受体（TCR）特异性如何指导CD25+ Treg的选择和功能。将确定自动反应性TCR在CD25+ Treg选择过程中与自肽相互作用的特异性，并还将定义CD25+ Treg的激活和效应函数的特异性要求。 AIM 3将评估自肽表达的变化如何有助于CD25+ Treg预防自身免疫性的能力。 CD25+ Treg是否会选择性地积聚在表达组织特异性抗原的淋巴结中。还将评估如何通过抗原呈递细胞在高水平上表现自肽的表现有助于评估CD25+ Treg预防自身免疫性的能力。这些研究将提供对免疫耐受性机制的基本见解，并进入可以导致自身免疫性疾病发展的过程。他们将提高我们对CD25+ Treg的发育和活动的理解，以及它们在新型治疗方法中的潜在应用。