Modulation of dendritic cell function in the pathogenesis of Inflammatory Bowel Diseases

7.项目摘要/摘要 免疫细胞对转化生长因子β的免疫调节和耐受作用的抵抗力是 自身炎症性疾病发病机制中的关键作用，包括炎症性肠病 (IBD)。虽然大部分的努力都是为了了解这种抗性在细胞中的 在获得性免疫系统中，类似的现象在先天免疫细胞中尚未被描述。粘膜 树突状细胞(DC)在免疫和耐受中都起着关键作用，进而在发病机制中也发挥着重要作用。 包括IBD在内的自身免疫性疾病。我们提供了新的证据来表明DC激活会导致 转化生长因子β耐药的发生，并确定两种可能的介体--IL-15/IL-15Rα 复合体和DAB2蛋白。我们开发了一种模拟DC特异性转化生长因子β抵抗的小鼠模型。 (TGFBR2ΔDC小鼠)，我们在其中表现出严重的胃肠道自体- 炎症性疾病。TGFBR2ΔDC的结肠炎发病机制需要CD_4~+和CD_8~+T细胞 伴有调节性T细胞隔间改变的小鼠(Treg；CD4+CD25-FoxP3+的扩增 Tregs和CD8+CD103+Tregs的减少)。利用开发的小鼠模型和分子工具，我们将 支持炎症性和/或感染性损伤导致DC激活导致升高的假设 白细胞介素15/白细胞介素15Rα复合体的表达及DAB2下调导致细胞转化生长因子β耐药 树突状细胞，一种导致Treg发育和功能受损的现象，以及 建立慢性肠炎模型。我们建议在以下几个方面解决这一假设 三个具体目标：(1)确定难治性转化生长因子β影响的肠道DC的初级亚群(S) 肠道炎症反应；(2)确定难治性肠炎的发病机制 活化DC对转化生长因子β的反应；(3)确定CD4+和CD8+的表型和功能损害 树突状细胞中由于转化生长因子β耐药而产生的Treg表型和功能。我们的工作 将探讨转化生长因子β耐药这一生理和临床上重要但尚未研究的现象。 由激活的树突状细胞获得。它将确定分子和细胞机制，并 在自体炎症性疾病的背景下描述这种抵抗的后果。

7. Project Summary/Abstract The development of resistance to immunomodulatory and tolerogenic effects of TGFβ in the immune cells is of key importance in the pathogenesis of auto-inflammatory disorders, including Inflammatory Bowel Diseases (IBD). While most effort has been directed towards understanding of such resistance in the cells of the adaptive immune system, similar phenomenon has not yet been described in the innate immune cells. Mucosal dendritic cells (DCs) play a crucial role in both immunity and tolerance, and by extension, in the pathogenesis of autoimmune disorders, including IBD. We provide new evidence to show that DC activation leads to a development of TGFβ resistance, and identify two putative mediators of this phenomenon – IL15/IL15Rα complex and DAB2 protein. We developed a mouse model mimicking DC-specific TGFβ resistance (TGFbR2ΔDC mice) in which we demonstrate severe consequences in form of gastrointestinal auto- inflammatory disorder. Both CD4+ and CD8+ T cells are required for the pathogenesis of colitis in TGFbR2ΔDC mice, which is accompanied with altered regulatory T cell compartment (Treg; expansion of CD4+CD25-FoxP3+ Tregs and reduction of CD8+CD103+ Tregs). With the developed mouse models and molecular tools, we will purse the hypothesis that DC activation by inflammatory and/or infectious insults result in elevated expression of IL15/IL15Rα complexes and downregulation of Dab2 that lead to TGFβ resistance in dendritic cells, a phenomenon resulting in impaired Treg development and function and an establishment of chronic intestinal inflammation. We propose to address this hypothesis in the following three specific aims: (1) To define the primary subset(s) of intestinal DCs affected with refractory TGFβ response during intestinal inflammation; (2) To characterize the mechanism responsible for the refractory response to TGFβ in activated DCs; (3) To define the phenotypic and functional impairment of CD4+ and CD8+ Treg phenotype and function that develops as a consequence of TGFβ resistance in dendritic cells. Our work will address a physiologically and clinically important, yet unexplored, phenomenon of TGFβ resistance acquired by activated dendritic cells. It will identify the molecular and cellular mechanisms responsible, and describe the consequences of such resistance in the context of autoinflammatory disorders.