Mechanisms of Peripheral Induction of T-cell Tolerance

T 细胞耐受的外周诱导机制

• 批准号: 8841651
• 负责人: Kristin A. Hogquist
• 金额: $ 167.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841651
• 关键词: Address; Affinity; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Vaccines; Cells; Clinical Trials; Clonal Deletion; Consensus; Development; Diabetes Mellitus; Diagnosis; Disease model; Early Diagnosis; Future; Glutamate Decarboxylase; Goals; Human; Immune Tolerance; Immune system; Immunotherapy; Insulin; Lead; Learning; Ligands; Lymphoid; Major Histocompatibility Complex; Mediating; Methods; Molecular; Monitor; Mus; Organ; Peptides; Peripheral; Phenotype; Population; Prevention; Process; Production; Proteins; Regulatory T-Lymphocyte; Relative (related person); Staging; T-Cell Receptor; T-Lymphocyte; Technology; Therapeutic; Thymus Gland; Tissues; Transgenic Mice; Vaccination; Vaccines; anergy; base; in vivo; innovation; innovative technologies; insight; mouse model; new technology; novel; pathogen; peripheral tolerance; prevent; programs; research study; response; tool; type I diabetic

DESCRIPTION (provided by applicant): Mechanisms that enforce T tolerance to self-antigens (self-Ags) in the secondary lymphoid organs (periphery) are critical for preventing development of autoimmune diseases, but can also limit the induction of desirable responses to self-Ags, as in the case of tumor vaccines, or to foreign Ags, as in the case of vaccines for pathogens. Much is known about the mechanisms that mediate peripheral T cell tolerance, but many fundamental questions remain, and developing an increased understanding of these processes will lead to an enhanced ability to manipulate tolerance for prevention or treatment of autoimmune diseases. This Program focuses on addressing these questions by examining CD4 and CD8 T cell tolerance mechanisms at the cellular and molecular levels. The Program includes four projects that all focus on tolerance to self-antigens in autoimmune disease models: Project 1. Analysis of peripheral tolerance in vivo (M. Jenkins) Project 2. Functional characterization of anergic T cells (D. Mueller) Project 3. Self reactivity in polyclonal T cell populations (K. Hogquist) Project 4. Mechanisms of self-Ag-induced non-responsiveness in CD8 T cells (M. Mescher) The overall Program goals are to gain new insights into fundamental mechanisms that lead to T cell tolerance and determine how and where these mechanisms act to enforce tolerance to self-antigens in mice and humans. Each project will apply innovative technologies to address these questions. Of particular note, new technology developed under this Program will allow analysis of self-reactive human T cells at a level not previously possible, and is likely to set the stage fr novel clinical trials. We anticipate that novel insights into mechanistic aspects of tolerance induction gained through the proposed studies will lead to new strategies for promoting tolerance in autoimmune diseases or avoiding tolerance during protective or therapeutic vaccination. RELEVANCE: Each project uses autoimmune disease models to study the cellular and molecular mechanisms for peripheral tolerance induction to self-antigens in T cells. Numerous interactions between the projects will provide synergy in achieving the overall Program goals. An Administrative Core will provide budgetary and scientific oversight and Core B (Autoimmune Mouse Core) will support all four of the projects. Project 1: Analysis of peripheral tolerance in vivo Project Leader: Marc Jenkins DESCRIPTION (provided by applicant): Most people do not suffer from autoimmunity despite the production of CD4+ T cells expressing T cell receptors (TCR) specific for self peptide (p):major histocompatibility complex II (MHCII) ligands. Many studies in TCR transgenic mouse models have shown that this is the case because these CD4+ T cells are deleted in the thymus or differentiate into anergic or suppressive regulatory T (Treg) cells in secondary lymphoid organs. Nevertheless, consensus on the relative contributions of these mechanisms to tolerance to all self antigens has not been reached. Fundamental questions therefore remain to be answered such as how efficient is thymic deletion, do anergic T cells exist, is the Treg cell repertoire really enriched for self p:MHCIl-specific cells, and which of these mechanisms fails during autoimmunity? We will answer these questions by studying polyclonal endogenous CD4+ T cells specific for self p:MHCII ligands using a sensitive p:MHCII tetramer-based cell enrichment method. In mice, we will determine whether T cells expressing TCRs with the highest affinities for ubiquitous self p:MHCII ligands are deleted, and whether some T cells specific for p:MHCII ligands derived from peripheral tissue-specific proteins expressed in the thymus under the control of the Autoimmune Regulator (AIRE) escape deletion but become anergic or differentiate into Treg cells in the secondary lymphoid organs. We will attempt to confirm these hypotheses in humans by direct ex vivo tracking of the number, function, and phenotype of insulin or glutamic acid decarboxylase p:MHCII-specific CD4+ T cells from normoglycemic or type 1 diabetic people. If successful, we will have learned how efficient thymic clonal deletion is, whether anergy exists as a tolerance mechanism, and if self-reactive T cell populations are enriched for Treg cells, all within normal polyclonal repertoires. These experiments could set the stage for future clinical trials to determine if self p:MHCII tetramer-based cell enrichment can be used as a tool for early diagnosis of diabetes or to monitor the efficacy of immunotherapy. RELEVANCE: This project focuses on the mechanisms of immune tolerance that prevent CD4+ T cells from causing autoimmunity. It will employ innovative T cell tracking technology to bridge the gap between mechanistic studies in mouse models and application to the human immune system. The approach described in this application could lead to new methods for diagnosing diabetes and monitoring immunotherapy.

描述（由申请人提供）：在次级淋巴器官（外周）中增强 T 对自身抗原（自身抗原）的耐受性的机制对于预防自身免疫性疾病的发展至关重要，但也可能限制诱导对自身抗原（如肿瘤疫苗）或外来抗原（如病原体疫苗）的理想反应。人们对介导外周 T 细胞耐受性的机制了解很多，但仍然存在许多基本问题，加深对这些过程的了解将增强操纵耐受性以预防或治疗自身免疫性疾病的能力。 该计划重点通过检查 CD4 和 CD8 T 细胞耐受性来解决这些问题 细胞和分子水平的机制。该计划包括四个项目，均侧重于 自身免疫性疾病模型中对自身抗原的耐受性： 项目1. 体内外周耐受性分析（M. Jenkins） 项目 2. 无反应性 T 细胞的功能表征 (D. Mueller) 项目 3. 多克隆 T 细胞群的自身反应性 (K. Hogquist) 项目 4. CD8 T 细胞自身 Ag 诱导无反应的机制 (M. Mescher) 总体计划目标是获得对导致 T 细胞的基本机制的新见解 耐受性并确定这些机制如何以及在何处发挥作用以增强小鼠和人类对自身抗原的耐受性。每个项目都将应用创新技术来解决这些问题。特别值得注意的是，根据该计划开发的新技术将能够以以前不可能的水平对人类自身反应性 T 细胞进行分析，并可能为新的临床试验奠定基础。我们预计，通过拟议的研究获得的对耐受诱导机制方面的新见解将带来促进自身免疫性疾病耐受或在保护性或治疗性疫苗接种期间避免耐受的新策略。 相关性：每个项目都使用自身免疫疾病模型来研究 T 细胞中对自身抗原的外周耐受诱导的细胞和分子机制。项目之间的大量互动将为实现总体计划目标提供协同作用。行政核心将提供预算和科学监督，核心 B（自身免疫小鼠核心）将支持所有四个项目。 项目1：体内外周耐受性分析 项目负责人：马克·詹金斯 描述（由申请人提供）：尽管产生了表达对自身肽（p）：主要组织相容性复合物 II（MHCII）配体具有特异性的 T 细胞受体（TCR）的 CD4+ T 细胞，但大多数人并未患有自身免疫性疾病。 TCR 转基因小鼠模型的许多研究表明，出现这种情况是因为这些 CD4+ T 细胞在胸腺中被删除，或者在次级淋巴器官中分化为无能或抑制性调节性 T (Treg) 细胞。然而，关于这些机制对所有自身抗原耐受的相对贡献尚未达成共识。因此，基本问题仍有待回答，例如胸腺缺失的效率如何，无反应性 T 细胞是否存在，Treg 细胞库是否真正富集自身 p:MHCI1 特异性细胞，以及这些机制中的哪一个在自身免疫期间失效？我们将通过使用敏感的基于 p:MHCII 四聚体的细胞富集方法研究对自身 p:MHCII 配体特异的多克隆内源性 CD4+ T 细胞来回答这些问题。在小鼠中，我们将确定表达对普遍存在的自身 p:MHCII 配体具有最高亲和力的 TCR 的 T 细胞是否被删除，以及某些对 p:MHCII 配体特异的 T 细胞是否在自身免疫调节器 (AIRE) 的控制下逃脱了删除，但变得无反应或分化为 Treg 细胞，这些 T 细胞衍生自在胸腺中表达的外周组织特异性蛋白。 次级淋巴器官。我们将尝试通过直接离体跟踪血糖正常或 1 型糖尿病患者的胰岛素或谷氨酸脱羧酶 p:MHCII 特异性 CD4+ T 细胞的数量、功能和表型来在人类中证实这些假设。如果成功，我们将了解到胸腺克隆删除的效率如何，无反应性是否作为一种耐受机制存在，以及自身反应性 T 细胞群是否富集 Treg 细胞，所有这些都在正常的多克隆库内。这些实验可以为未来的临床试验奠定基础，以确定基于 p:MHCII 四聚体的自身细胞富集是否可以用作糖尿病早期诊断或监测免疫疗法疗效的工具。 相关性：该项目重点研究防止 CD4+ T 细胞引起自身免疫的免疫耐受机制。它将采用创新的 T 细胞追踪技术来弥补小鼠模型的机制研究与人类免疫系统应用之间的差距。该申请中描述的方法可能会带来诊断糖尿病和监测免疫治疗的新方法。