Antigen Presentation and T cell Programming in Human Autoimmune Diseases

描述（由申请人提供）：抗原呈递是每个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。参加PPG的七名研究人员在专业领域高度互补，并形成了一个有凝聚力的多学科项目。总体假设是，自身免疫性疾病的发展和进展是由抗原呈递细胞（APC）的特化群体控制的，所述APC在诱导不同的效应和调节T细胞程序中起不同的作用。该团队强调直接研究自身免疫性疾病患者的APC - T细胞相互作用，特别是多发性硬化症（MS），并将这些人类免疫学研究与相关动物模型的深入机制研究相结合。在上一个资助期间，该小组开发了一种新型的基于T细胞的技术平台，用于自身免疫性疾病中T细胞功能的多重研究。该技术能够在亚纳升体积的威尔斯孔中共培养单个T细胞与成熟树突状细胞，用于细胞因子分泌和表面标志物的多维表征。此外，可以用机器人装置回收应答T细胞以表征转录程序。这项技术将被所有研究人员用来检查T细胞与不同APC群体相互作用的功能后果。该团队将解决该领域的一个长期挑战，并确定MS患者和健康受试者中自身反应性T细胞之间的功能和分子差异。MS CNS病变和动物模型的研究将研究T细胞与不同APC群体的相互作用如何导致靶器官中慢性炎症微环境的形成。特别令人感兴趣的是T细胞、B细胞和基质细胞之间的复杂相互作用，其导致CNS中异位淋巴滤泡的形成。 上一个资助期的研究表明，Th 17细胞表达podoplanin（PDPN），这是一种与B细胞和成熟树突状细胞上的CLEC-2相互作用的表面分子。基于抗体的PDPN功能阻断可防止异位淋巴滤泡的形成，现在将在MS病变和条件性基因敲除小鼠中研究这些分子的功能。该计划是高度协同的基础上，我们专注于在自身免疫领域的一个重要问题，我们的高度协作的方法整合了一个独特的研究人员团队，具有分子和细胞免疫学，生物物理学和工程学的专业知识，以研究疾病机制在自身免疫与尖端技术。

DESCRIPTION (provided by applicant): Antigen presentation is an integral component of every autoimmune disease process, and thus represents an important scientific and clinical problem. The seven investigators who come together in this PPG have highly complementary areas of expertise and have formed a cohesive, multidisciplinary program. The overarching hypothesis is that the development and progression of autoimmune diseases are controlled by specialized populations of antigen-presenting cells (APCs) that serve distinct roles in the induction of different effector and regulatory T cell programs. The team emphasizes direct investigation of APC - T cell interactions in patients with autoimmune diseases, in particular multiple sclerosis (MS), and integrates these human immunological studies with in-depth mechanistic studies in relevant animal models. During the previous funding period, the group developed a novel nanowell-based technology platform for multiplexed investigation of T cell function in autoimmune diseases. The technology enables co-culture of single T cells with mature dendritic cells in wells of subnanoliter volume for multi-dimensional characterization of cytokine secretion and surface markers. Furthermore, responding T cells can be recovered with a robotic device for characterization of transcriptional programs. This technique will be used by all investigators to examine the functional consequences of T cell interactions with distinct populations of APC. The team will address a long-standing challenge in the field and define the functional and molecular differences between self-reactive T cells in patients with MS and healthy subjects. Studies in MS CNS lesions and animal models will examine how the interaction of T cells with different populations of APCs results in the formation of chronic inflammatory microenvironments in the target organ. Of particular interest is the complex interplay between T cells, B cells and stromal cells that results in the formation of ectopic lymphoid follicles in the CNS. Studies during the previous funding period have shown that Th17 cells express podoplanin (PDPN), a surface molecule that interacts with CLEC-2 on B cells and mature dendritic cells. Antibody-based blockade of PDPN function prevents formation of ectopic lymphoid follicles, and the function of these molecules will now be studied in MS lesions and conditional knock-out mice. The program is highly synergistic based on our focus on an important problem in the autoimmunity field, and our highly collaborative approach integrates a unique team of investigators with expertise in molecular and cellular immunology, biophysics, and engineering to investigate disease mechanisms in autoimmunity with cutting-edge technologies.