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中不可或缺的组成部分，因此是一个重要的科学和临床问题。在这个PPG中聚集的七名调查人员拥有高度互补的专业领域，并形成了一个具有凝聚力的多学科计划。最重要的假设是，自身免疫性疾病的发展和进展是由特定的抗原提呈细胞(APC)群体控制的，APC在诱导不同的效应器和调节性T细胞程序方面发挥着不同的作用。该团队强调直接研究自身免疫性疾病患者，特别是多发性硬化症(MS)患者的APC-T细胞相互作用，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。在之前的资助期间，该小组开发了一个新的基于纳米细胞的技术平台，用于对自身免疫性疾病中T细胞功能的多路研究。该技术使单个T细胞与成熟树突状细胞在亚纳升体积的井中共培养，以用于细胞因子分泌和表面标记的多维表征。此外，反应的T细胞可以用机器人设备恢复，以确定转录程序的特征。这项技术将被所有研究人员用来检查T细胞与不同的APC人群相互作用的功能后果。该团队将解决该领域的长期挑战，并确定多发性硬化症患者和健康受试者自身反应性T细胞之间的功能和分子差异。在MS CNS损害和动物模型中的研究将检查T细胞与不同群体的APC相互作用如何导致靶器官中慢性炎症微环境的形成。尤其令人感兴趣的是T细胞、B细胞和基质细胞之间复杂的相互作用，导致中枢神经系统异位淋巴滤泡的形成。上一次资助期间的研究表明，Th17细胞表达足阳素(PDPN)，这是一种在B细胞和成熟树突状细胞上与CLEC-2相互作用的表面分子。基于抗体的PDPN功能阻断可以防止异位淋巴滤泡的形成，这些分子的功能现在将在MS病变和条件性基因敲除小鼠中进行研究。该计划基于我们对自身免疫领域一个重要问题的关注，具有高度的协同性，我们高度协作的方法整合了一支独特的研究团队，他们拥有分子和细胞免疫学、生物物理学和工程学方面的专业知识，利用尖端技术研究自身免疫的疾病机制。

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.