Regulation of T cell immunity by stromal cells in autoimmune tissue inflammation

众所周知，中枢神经系统（CNS）的白细胞浸润是中枢神经系统疾病的关键早期步骤。 发展的脱髓鞘自身免疫性疾病，多发性硬化症（MS），但机制的细节 对这一过程的了解仍然很少。在靶向治疗中阻断白细胞浸润和CNS破坏 方式仍然是一个重大的临床挑战。长期目标是开发治疗方法， 免疫耐受和控制自身免疫介导靶器官破坏。这项建议的目的是 以确定基质细胞如何调节中枢神经系统的自身免疫性炎症。基质细胞产生炎症 微环境，吸引T细胞和抗原呈递细胞（APC）进入CNS， 网状结构，浸润性白细胞在其上爬行，并通过 与Th 17细胞的相互作用此外，基质细胞可以作为APC发挥作用，并调节活化的T细胞的功能。 近距离的细胞。核心假设是基质细胞网络对于形成 这一假设是基于文献中出现的证据， 申请人实验室生成的初步数据。拟议研究的理由是， 阐明了基质细胞与T细胞和APC在血脑屏障上相互作用的机制， 中枢神经系统实质可以阐明这一致病过程的机理。两个具体目标将是 为了检验这一假设，我们进行了以下研究：1）确定基质细胞表达PDPN在白细胞浸润中的作用 的CNS。和2）阐明炎症CNS中基质细胞-白细胞串扰的影响。的一部分 第一个目标，将研究MS患者和健康受试者的人脑组织，以评估相互作用 白细胞和表达PDPN的基质细胞之间的关系。此外，新的条件敲除小鼠 将用于评估基质细胞的PDPN表达和树突状细胞的CLEC-2表达以及 B细胞影响EAE期间CNS的白细胞浸润。在第二个目标中，自身免疫组织的影响 将评价炎症对基质细胞与T细胞和APC相互作用的影响。此外，该机制通过 炎症环境将FRC从免疫抑制细胞转化为促炎细胞， 审问。这项研究是创新的，因为基质细胞对肿瘤发病机制的贡献， MS是一个研究不足的领域，PDPN-CLEC-2轴在炎症组织白细胞浸润中的作用 以前没有提到过。这项研究是有意义的，因为阐明的机制， 基质细胞影响APC和T细胞功能可能为干预提供新的机会。

It is well established that leukocyte infiltration of the central nervous system (CNS) is a critical early step in the development of the demyelinating autoimmune disease, multiple sclerosis (MS) however the mechanistic details of this process remain poorly understood. Blocking leukocyte infiltration and destruction of the CNS in a targeted manner remains a significant clinical challenge. The long-term objectives are to develop therapeutics that restore immune tolerance and control autoimmune-mediated destruction of target organs. The obiective of this proposal is to define how stromal cells regulate autoimmune inflammation of the CNS. Stromal cells create inflammatory microenvironments, attract T cells and antigen presenting cells (APCs) into the CNS, create three-dimensional reticular structures that infiltrating leukocytes crawl on, and produce proinflammatory cytokines through interactions with Th17 cells. Moreover, stromal cells can function as APCs and regulate the function of activated T cells in close proximity. The central hvpothesis is that a stromal cell network is essential for the formation of chronic inflammatory lesions in MS. This hypothesis is based on emerging evidence from the literature and preliminary data generated in the applicants' laboratories. The rationale for the proposed research is that elucidating the mechanisms by which stromal cells interact with T cells and APCs at the blood brain barrier and in the CNS parenchyma may illuminate mechanistic insight into this pathogenic process. Two specific aims will be carried out to test this hypothesis: 1) Define the role of PDPN expression by stromal, cells in leukocyte infiltration of the CNS. and 2) Elucidate the impact of stromal cell-leukocyte cross-talk in the inflamed CNS. As part of the first aim, human brain tissue from MS patients and healthy subjects will be studied to evaluate the interactions between leukocytes and PDPN-expressing stromal cells in lesions. In addition, novel conditional knockout mice will be used to evaluate whether PDPN expression by stromal cells and CLEC-2 expression by dendritic ceils and B ceils affects leukocytic infiltration of the CNS during EAE. In the second aim the impact of autoimmune tissue inflammation on stromal cell interactions with T cells and APCs will be evaluated. Furthermore, the mechanism by which the inflammatory milieu converts FRCs from immunosuppressive to proinflammatory cells will be interrogated. The proposed research is innovative because the contribution of stromal cells to the pathogenesis of MS is an understudied field and the role ofthe PDPN-CLEC-2 axis in leukocyte infiltration of inflamed tissues has not been previously addressed. The study is significant because elucidation ofthe mechanisms by which stromal cells influence APC and T cell function may offer new opportunities for intervention.