Antigen Presentation in Human Autoimmune Diseases

人类自身免疫性疾病中的抗原呈递

• 批准号: 7897291
• 负责人: Kai W Wucherpfennig
• 金额: $ 6.44万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2010-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897291
• 关键词: Antigen; Presentation; Human; Autoimmune; Diseases

DESCRIPTION (provided by applicant): This PPG was initiated in 1998 in response to a RFA for "Human Immunology Centers of Excellence" and has a well-defined, central focus on the mechanisms of antigen presentation and T cell recognition in human autoimmune diseases, in particular multiple sclerosis (MS) and type 1 diabetes (T1D). Antigen presentation is an integral component of every autoimmune disease process and thus represents an important scientific and clinical problem. The six investigators who come together in this PPG have highly complementary areas of expertise and have formed a cohesive, multidisciplinary program under the guidance of the Program Director. During the present funding period this group has been highly productive, documented by numerous joint publications that have had a significant impact on the field. The overarching hypothesis is that the development and progression of autoimmune diseases are controlled by specialized populations of antigen presenting cells that serve distinct roles in tolerance induction versus propagation of autoimmunity. There are four major themes that connect the individual projects of this PPG. A previously unrecognized population of lymph node stromal cells with functional similarities to thymic medullary epithelial cells induces peripheral tolerance by expression of a wide variety of peripheral tissue antigens, and the biology of this cell population and potential therapeutic applications will be investigated (Projects 1 & 2). The role of self-reactive B cells as efficient antigen presenting cells for T cells with the same specificity will be examined in a new mouse model that resembles a severe subtype of MS. New technologies, including a nanowell technique for functional definition of B cell populations at a single cell level and fluorescent self-antigen tetramers, will be used to define the functional properties of self-reactive B cells in patients with MS and T1D (Projects 3 & 4). Particular emphasis will be placed on definition of the antigen presentation mechanisms responsible for T cell differentiation into regulatory and effector T cell subsets (Projects 1-3) and on characterization of the unique recognition and signaling properties of self-reactive T cells isolated from patients with MS and T1D (Projects 1 & 4). During the past two funding cycles, the program has already had an impact on the development of therapeutics, and the areas of investigation for the next funding period offer a significant number of new opportunities. PROJECT 1: Antigen Presentation to Self-reactive T cells in Human Autoimmune Diseases (PL: Kai W. Wucherpfennig, MD, PhD) DESCRIPTION (provided by applicant): The goal of the project is to define the antigen presentation and T cell recognition mechanisms responsible for the activation of myelin-specific CD4 T cells in MS. During this funding period, the Project Leader's (PL) lab determined the crystal structure of the first human autoimmune TCR and identified an unusual TCR binding topology. Biochemical studies demonstrated a low affinity interaction of this TCR with its self-peptide/MHC complex, consistent with the suboptimal binding mode observed in the structure. Such a suboptimal binding mode may facilitate escape from tolerance induction in the thymus and periphery because the relevant antigen presenting cells express limiting quantities of self-antigen. Transgenic mice that express this TCR and the human MHC restriction element nevertheless develop spontaneous autoimmunity at a high incidence, indicating that these T cells have recognition/signaling mechanisms that at least partially compensate for the altered TCR interaction with self-peptide/MHC. Imaging studies demonstrated substantial differences in the organization of immunological synapses formed by two different myelin-specific human T cell clones compared to two anti-viral T cell clones. During the next funding period, we will determine how the altered TCR recognition properties affect the formation of immunological synapses and resulting signaling events. In Aim 1, we will define the mechanisms of immunological synapse formation by examining the kinetics of synapse formation, the recruitment of key signaling molecules, the duration of signaling as well as the mechanisms that terminate signaling by TCR internalization. Our hypothesis is that the suboptimal TCR binding properties delay TCR transport to the synapse center where TCR is internalized, thus extending the duration of the initially weaker activation signal. In Aim 2, we will examine how these changes quantitatively modify the contribution of particular signaling pathways in self-reactive versus anti-viral T cells, with the goal of identifying signaling molecules that are critical for the activation of self-reactive T cells but dispensable for anti-viral T cells. In Aim 3, we will examine whether tolerance can nevertheless be induced for such T cells by targeted delivery of the self-peptide via an antibody-peptide fusion protein to lymph node stromal cells specialized in peripheral tolerance.

描述（由申请人提供）：该PPG于1998年启动，以响应“人类免疫学卓越中心”的RFA，并明确重点关注人类自身免疫性疾病（特别是多发性硬化症（MS）和1型糖尿病（T1 D））中的抗原呈递和T细胞识别机制。抗原呈递是每种自身免疫性疾病过程的组成部分，因此代表了重要的科学和临床问题。在这个PPG中走到一起的六名研究人员具有高度互补的专业领域，并在项目主任的指导下形成了一个有凝聚力的多学科项目。在本供资期内，该小组工作卓有成效，许多联合出版物都记录了这一点，这些出版物对实地产生了重大影响。总体假设是，自身免疫性疾病的发展和进展由抗原呈递细胞的特化群体控制，所述抗原呈递细胞在耐受诱导与自身免疫性传播中起不同作用。有四个主要主题连接这个PPG的各个项目。一个以前未被认识到的淋巴结基质细胞群与胸腺髓质上皮细胞功能相似，通过表达多种外周组织抗原诱导外周耐受，将研究该细胞群的生物学和潜在的治疗应用（项目1和2）。将在类似于MS的严重亚型的新小鼠模型中检查自身反应性B细胞作为具有相同特异性的T细胞的有效抗原呈递细胞的作用。新技术，包括用于在单细胞水平上功能定义B细胞群的细胞技术和荧光自身抗原四聚体，将用于定义MS和T1 D患者中自身反应性B细胞的功能特性（项目3和4）。将特别强调负责T细胞分化为调节性和效应性T细胞亚群的抗原呈递机制的定义（项目1-3），以及从MS和T1 D患者中分离的自身反应性T细胞的独特识别和信号传导特性的表征（项目1和4）。在过去的两个资助周期中，该计划已经对治疗学的发展产生了影响，下一个资助期的研究领域提供了大量的新机会。 项目1：人类自身免疫性疾病中自身反应性T细胞的抗原呈递（PL：Kai W。Wucherpfennig，医学博士，哲学博士） 描述（由申请人提供）：该项目的目标是定义负责MS中髓鞘特异性CD 4 T细胞活化的抗原呈递和T细胞识别机制。在此资助期间，项目负责人（PL）实验室确定了第一个人类自身免疫TCR的晶体结构，并确定了一种不寻常的TCR结合拓扑结构。生物化学研究表明该TCR与其自身肽/MHC复合物的低亲和力相互作用，与在结构中观察到的次优结合模式一致。这种次优结合模式可能有助于逃避胸腺和外周中的耐受诱导，因为相关抗原呈递细胞表达有限量的自身抗原。然而，表达这种TCR和人MHC限制性元件的转基因小鼠以高发生率发展自发性自身免疫，表明这些T细胞具有至少部分补偿改变的TCR与自身肽/MHC相互作用的识别/信号传导机制。成像研究表明，两种不同的髓鞘特异性人类T细胞克隆相比，两种抗病毒T细胞克隆形成的免疫突触的组织有很大的差异。在下一个资助期间，我们将确定改变的TCR识别特性如何影响免疫突触的形成和由此产生的信号事件。在目标1中，我们将通过检查突触形成的动力学、关键信号分子的募集、信号传导的持续时间以及通过TCR内化终止信号传导的机制来定义免疫突触形成的机制。我们的假设是，次优的TCR结合特性延迟TCR转运到TCR内化的突触中心，从而延长最初较弱的激活信号的持续时间。在目标2中，我们将研究这些变化如何定量地改变自身反应性T细胞与抗病毒T细胞中特定信号通路的贡献，目的是确定对自身反应性T细胞活化至关重要但对抗病毒T细胞至关重要的信号分子。在目的3中，我们将检查是否仍然可以通过将自身肽经由抗体-肽融合蛋白靶向递送至专门用于外周耐受的淋巴结基质细胞来诱导对这样的T细胞的耐受。