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: 7663631
• 负责人: ANDREW J CATON
• 金额: $ 41.83万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663631
• 关键词: Address; Adoptive Transfer; Affinity; Antibody Formation; Antigen-Presenting Cells; Antigens; Arthritis; Autoimmune Diseases; Autoimmunity; Biological Models; CD4 Positive T Lymphocytes; Cell Count; Cell physiology; Cells; Cellular biology; Data; Development; Diagnosis; Diagnostic; Environment; Failure; Frequencies; Goals; Hemagglutinin; IL2RA gene; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Inflammatory; Mus; Peptides; Play; Process; Public Health; Regulation; Rheumatoid Arthritis; Role; Shapes; Signal Transduction; Specificity; T-Cell Receptor; T-Lymphocyte; Therapeutic; Tissues; Transgenes; Transgenic Mice; Variant; Viral; Virus; autoimmune arthritis; cancer transplantation; human disease; in vivo; influenzavirus; insight; neuronal cell body; novel; pathogen; prevent; promoter; public health relevance; response; thymocyte

DESCRIPTION (provided by applicant): This project's goal is to use a well-characterized model system to define processes governing the formation and activity of CD4+CD25+Foxp3+ regulatory T (Treg) cells. The proposal will make use of existing lineages of transgenic mice expressing the influenza virus hemagglutinin (HA) under the control of a variety of promoters (HA Tg mice) and/or HA-specific T cell receptors with varying affinities and specificities for the HA (TCR Tg mice). By analyzing double transgenic mice co-expressing HA-specific TCRs and neo-self HA peptides (TCRxHA Tg mice), we have shown that highly specific interactions with HA-derived peptides can induce thymocytes to undergo selection to become Treg cells that suppress conventional CD4+ T (Tconv) cell responses in vitro, and can modify immune responses in vivo. We have shown that the formation of these Treg cells is highly sensitive to variations in the amount of the HA that is expressed in different HA Tg lineages, and that expression of HA selectively by antigen presenting cells in one of these lineages (designated HACII mice) induces the spontaneous development of inflammatory arthritis in TCRxHACII mice despite the presence of antigen-specific Treg cells. We will use this unique model system to examine how TCR specificity directs Treg cell formation and determines the capacity of Treg cells to modulate anti-self and anti-viral immune responses. In Aim 1 we will examine how TCR recognition of self-peptides shapes Treg repertoire formation. We will modulate the reactivity of the TCR for self-peptides and determine the effects on thymic Treg cell development in TCRxHA Tg mice, and will use adoptive transfer approaches to examine the development of Treg cells in the periphery of HA Tg mice under various conditions. In Aim 2 we will examine how Treg specificity for self-peptides shapes anti-viral immunity. We will analyze the ability of Treg cells from TCRxHA Tg mice to modulate antibody responses to influenza viruses with which they possess varying degrees of crossreactivity, and examine HA Tg mice that do not co-express TCR transgenes for their frequencies of virus- specific CD4+ Treg and Tconv cells. In Aim 3 we will determine how TCR specificity impacts the ability of Treg cells to prevent autoimmune arthritis. We will either deplete Treg cells, or add Treg cells with varying degrees of reactivity with the HA to pre-arthritic TCRxHACII mice, and determine the effects on cellular processes that accompany arthritis development. We will also analyze the expansion and differentiation of Treg cells with varying degrees of reactivity for the HA following transfer into HACII or TS1xHACII mice. These studies will provide fundamental insights into the mechanisms of immune repertoire formation and tolerance. They will enhance our understanding of the role immune regulation plays in anti-viral immunity and how its failure can contribute to autoimmunity, and will enhance the ability of Treg cells to b exploit in diagnostic therapeutic settings. PUBLIC HEALTH RELEVANCE: Regulatory T cells play an vital role in preventing the immune system from mounting harmful responses to the body's cells and tissues, such as can occur in autoimmune diseases. These cells can also modify the activity of the immune system in settings such as infection, transplantation and cancer. This proposal uses genetically-modified mice to analyze mechanisms and cellular processes than govern the development and activity of regulatory T cells, and to develop novel insights into regulatory T cell biology that will facilitate their application for diagnosis and therapy of human diseases.

描述（由申请人提供）：该项目的目标是使用良好的模型系统来定义管理CD4+CD25+FOXP3+调节t（Treg）单元格的形成和活动的过程。该提案将利用在各种启动子（HA TG小鼠）和/或HA特异性T细胞受体的控制下，表达流感病毒血凝素（HA）的转基因小鼠的现有谱系，其对HA（TCR TG TG小鼠）具有不同的亲和力和特异性。通过分析双转基因小鼠共表达HA特异性TCR和新自我HA肽（TCRXHA TG小鼠），我们已经表明，与HA衍生肽的高度特异性相互作用可以诱导胸腺细胞诱导选择成为TREG的细胞，从而抑制常规CD4+ T（TCONV）细胞（TCONV）细胞（TCONV）的细胞反应，并可以在Vistro中进行不合时宜。我们已经表明，这些Treg细胞的形成对在不同的HA TG谱系中表达的HA的数量的变化高度敏感，并且通过抗原呈递细胞在这些谱系之一（指定的HACII小鼠）中选择性地表达HA（指定的HACII小鼠）在TCRXHACII静止症中的自发性发育诱发了抗炎细胞的自发发展。我们将使用这种独特的模型系统来检查TCR特异性如何指导Treg细胞形成，并确定Treg细胞调节抗自我和抗病毒免疫反应的能力。在AIM 1中，我们将研究TCR识别自肽的形状Treg曲目形成。我们将调节TCR对自肽的反应性，并确定对TCRXHA TG小鼠中胸腺Treg细胞发育的影响，并将采用过继转移方法检查在各种条件下HA TG小鼠外围的Treg细胞的发育。在AIM 2中，我们将研究对自肽的特异性特异性如何塑造抗病毒免疫。我们将分析TCRXHA TG小鼠的Treg细胞的能力，调节对具有不同程度的交叉反应性的流感病毒反应的抗体反应，并检查不为其频率的病毒 - 特异性CD4+ TREG和TCONV细胞的HA TG小鼠。在AIM 3中，我们将确定TCR特异性如何影响Treg细胞预防自身免疫性关节炎的能力。我们要么耗尽treg细胞，要么添加与HA的反应性不同程度的Treg细胞到关节炎前TCRXHACII小鼠，并确定对关节炎发育伴随的细胞过程的影响。我们还将分析转移到HacII或TS1XHACII小鼠后HA的反应性不同程度的Treg细胞的膨胀和分化。这些研究将提供对免疫曲目形成和耐受性机制的基本见解。它们将增强我们对免疫调节在抗病毒免疫中的作用以及其失效如何有助于自身免疫性的理解，并将增强Treg细胞在诊断治疗环境中的利用能力。 公共卫生相关性：调节性T细胞在防止免疫系统对人体细胞和组织的有害反应上加快有害反应中起着至关重要的作用，例如自身免疫性疾病中可能发生。这些细胞还可以在感染，移植和癌症等环境中改变免疫系统的活性。该建议使用遗传改性小鼠来分析机制和细胞过程，而不是控制调节性T细胞的发育和活性，并开发了对调节性T细胞生物学的新见解，这些见解将促进其在人类疾病的诊断和治疗中的应用。