Regulation of Th17 Functions in Autoimmune CNS Inflammation

描述(申请人提供)：多发性硬化症(MS)是一种衰弱的自身免疫性神经疾病。Th17细胞已成为慢性自身免疫性疾病发病的关键驱动因素，并在MS患者中增加。在实验性自身免疫性脑脊髓炎(EAE)的MS小鼠模型中，Th17细胞也是推动中枢神经系统炎症的关键。我们以前的工作表明，Th17细胞的增殖和分化依赖于IL-23的信号，从而能够在EAE中驱动炎症反应。 尽管Th17细胞大多被认为是产生IL-17的细胞，但它们还有许多额外的功能，而且IL-17并不总是足以驱动疾病。然而，IL-23是至关重要的，我们的目标是了解IL-23在炎症性疾病中促进Th17功能的具体机制。我们最近发现了一种新的整合素，它是由效应Th17细胞以IL-23依赖的方式表达的，是EAE所必需的。已发表的报告描述了这种整合素在包括MS在内的许多人类炎症性疾病中的表达增加。然而，对于它在T细胞，特别是Th17细胞中的功能重要性，几乎一无所知。总而言之，这些数据形成了我们的中心假设的基础，即这种整合素是一种由IL-23驱动的关键分子，参与决定自身免疫Th17细胞的炎症活动。我们现在的目标是询问其表达在Th17介导的炎症中的作用，从而验证该整合素作为Th17导向的新的治疗靶点。

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is a debilitating autoimmune neurological disease. Th17 cells have emerged as key drivers of pathogenesis in chronic autoimmune disease and are increased in MS patients. Th17 cells are also critical for driving CNS inflammation in the murine model of MS, experimental autoimmune encephalomyelitis (EAE). Our previous work demonstrated that Th17 cells are dependent on signals from IL-23 for their proliferation and differentiation into effector cells capable of driving inflammation in EAE. Although Th17 cells are mostly considered as IL-17 producers, they have many additional functions and IL-17 is not always sufficient to drive disease. However, IL-23 is critical, and our goal is to understand the specific mechanisms by which IL-23 promotes Th17 functions in inflammatory disease. We have recently discovered a novel integrin that is expressed by effector Th17 cells in an IL-23-dependent manner, and required for EAE. Published reports describe increased expression of this integrin in a number of human inflammatory diseases, including MS. However, almost nothing is known about its functional importance in T cells, and in particular Th17 cells. Collectively, these data form the basis for our central hypothesis that this integrin is a key IL-23-driven molecule involved in determining the inflammatory activity of autoimmune Th17 cells. We now aim to interrogate the role of its expression in Th17-mediated inflammation, and thereby to validate this integrin as a novel Th17-directed therapeutic target.