Regulatory role of CD90+ stromal cells in Th1/Th17 activity in Crohn's Disease

描述（由申请人提供）：克罗恩病（CD）的免疫发病机制的特点是对肠道菌群的先天和适应性免疫反应的免疫调节缺陷，导致炎症T辅助细胞（Th）1和Th17反应失控，其机制尚不清楚。虽然已经提出专业抗原呈递细胞（APCs）通过myd88依赖性toll样受体（TLRs）的促炎激活是其机制，但在CD动物模型中，专业抗原呈递细胞（APCs）的致病性反应的消除只会导致肠道平衡的强烈改善，而不是完全恢复。这种不完全的反应提出了以下问题：非专业apc如CD90+基质细胞（肠道固有层中丰富的细胞类型）在这些过程中起什么作用？我们的目的是确定tlr依赖性和独立的信号过程是如何在人肠结肠粘膜CD90+基质细胞（肌成纤维细胞/成纤维细胞，CMFs）参与Th1/Th17肠道平衡的调节。和确定这些过程中断在CD。我们的中心假设是一个开关CD90 + (myo)从免疫抑制成纤维细胞功能(IL-6lowPD-L1 +)对炎症(IL-6highPD-L1low)是一个关键过程的持久性Th1 / Th17反应CD。这一假说的基本原理是正常(N -) CD90 + cmf抑制不良Th1型急性炎症介导通过PD-L1(细胞程序性死亡配体1)和刺激代CD4 +调节性T细胞。相反，我们的数据表明CD-CMFs表现出根本改变的表型：它们具有Th1抑制分子PD-L1的低表达，产生CD4+调节性T细胞的能力降低，基础和TLR诱导的IL-6分泌上调，aTh17促进细胞因子。我们使用成纤维细胞特异性MyD88条件敲除小鼠的初步体内数据也支持CMFs在调节Th1/Th17反应中的重要性。我们将通过解决以下具体目标来验证我们的假设：(1)确定人类CD-CMFs的促炎激活在调节Th1/Th17反应中的作用；(2)阐明CD-CMFs的炎性（PD- L1lowIL-6high）激活机制；(3)确定CMF炎症激活在CD小鼠结肠炎发生中的病理生理作用。这个项目意义重大

DESCRIPTION (provided by applicant): The immunopathogenesis of Crohn's Disease (CD) is characterized by defective immunoregulation of innate and adaptive immune responses toward intestinal microflora, leading to uncontrolled inflammatory T helper cell (Th)1 and Th17 responses via a yet unknown mechanism. Although the proinflammatory activation of professional antigen presenting cells (APCs) thorough MyD88-dependent toll like receptors (TLRs) has been proposed as the mechanism, abrogation of pathogenic responses of professional APCs leads only to a strong improvement, but not full restoration, of the intestinal balance in animal models of CD. This incomplete response raises the question: what role do non-professional APCs such as CD90+ stromal cells, an abundant cell type in the gut lamina propria, plays in these processes? Our objective is to identify how TLR-dependent and independent signaling processes in human intestinal colonic mucosal CD90+ stromal cells (myofibroblasts/fibroblasts, CMFs) are involved in the regulation of Th1/Th17 intestinal balance, and determine how these processes are disrupted in CD. Our central hypothesis is that a switch in the CD90+ (myo)fibroblast function from immunosuppressive (IL-6lowPD-L1+) toward inflammatory (IL-6highPD-L1low) is a key process in the persistence of the Th1/Th17 responses in CD. The rationale for this hypothesis is that normal (N-) CD90+ CMFs suppress undesirable Th1 type acute inflammation mediated via PD-L1 (Programmed cell death 1 ligand 1) and stimulate the generation of CD4+ regulatory T cells. In contrast, our data suggest that CD-CMFs display a fundamentally altered phenotype: they have low expression of Th1 suppressive molecule PD-L1, reduced ability to generate CD4+ regulatory T cells and upregulated basal and TLR inducible IL-6 secretion, aTh17 promoting cytokine. Our initial in vivo data with use of fibroblast-specific MyD88 conditional knockout mice also support the importance of CMFs in the regulation of the Th1/Th17 responses. We will test our hypothesis by addressing the following specific aims: (1) Define role of the proinflammatory activation of human CD-CMFs in the regulation of Th1/Th17 responses; (2) Elucidate mechanism(s) responsible for the inflammatory (PD- L1lowIL-6high) activation of CD-CMFs; (3) Determine the pathophysiological role CMF inflammatory activation to the development of CD murine colitis. This project is highly significant to the integrative global research priorities in IBD: it will elucidate previously unexplored interactions between innate and adaptive immune components contributing to the initiation and progression of CD. We expect to provide key mechanistic insights into the role of CMFs in regulation of the Th1/Th17 responses during CD immunopathogenesis. As a translational project, we expect to identify new therapeutic targets for effective treatments of CD.