Antigen Presentation in Human Autoimmune Diseases

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，并具有明确的，集中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（T1D）的抗原呈递和T细胞识别机制。抗原呈递是每一个自身免疫性疾病过程的组成部分，因此是一个重要的科学和临床问题。这六名研究人员在PPG中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。在目前的供资期间，这一群体的工作成果很高，许多对该领域产生重大影响的联合出版物记载了这一点。总的假设是，自身免疫性疾病的发生和发展是由抗原提呈细胞的特殊群体控制的，这些细胞在自身免疫的耐受性诱导和增殖中起着不同的作用。这个PPG的各个项目有四个主要的主题。一种以前未被认识的淋巴基质细胞群与胸腺髓上皮细胞功能相似，通过表达多种外周组织抗原诱导外周耐受，该细胞群的生物学特性和潜在的治疗应用将被研究（项目1和2）。将在一种类似多发性硬化症严重亚型的新小鼠模型中检验自体反应性B细胞作为具有相同特异性的T细胞有效抗原提呈细胞的作用。新技术，包括用于单细胞水平B细胞群功能定义的纳米孔技术和荧光自体抗原四聚体，将用于定义多发性硬化症和T1D患者自体反应性B细胞的功能特性（项目3和4）。重点将放在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T1D患者中分离的自反应性T细胞的独特识别和信号特性的表征（项目1和4）。在过去的两个资助周期中，该项目已经对治疗学的发展产生了影响，下一个资助周期的研究领域提供了大量的新机会。

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.