TLRs in Host Commensal Interactions

描述（由申请人提供）：炎症性肠病以肠道免疫反应失调为特征。尽管最近的进展强调了共生细菌、先天免疫系统、骨髓细胞（树突状细胞（DC）和巨噬细胞）、TH17细胞和调节性T细胞（Tregs）的关键作用，但诱导致病性T细胞反应的机制仍然不明确。这些最近的发现带来了一个新的研究重点，包括关键先天免疫信号通路的表征及其在致病性T细胞反应发展中的作用。特别是，对肠道中TH17反应的分析已经阐明了这些细胞产生的细胞因子在结肠炎发展中的致病和保护作用。同样，越来越多的证据表明，不同的先天信号通路（例如，il -23驱动，与TGFb和il -6驱动）可能在致病性与非致病性或保护性Th17反应的产生中发挥不同的作用。在本提案中，我们将研究先天免疫感知途径在肠道中启动致病性T细胞反应中的作用。具体来说，我们将研究IL-6、IL-1和TGFb在TH1和TH17反应产生中的作用，以及它们在结肠炎发展中的作用。我们还将研究导致肠道中TH17反应产生的不同先天途径的作用。

DESCRIPTION (provided by applicant): Inflammatory Bowel Diseases are characterized by disregulated immune responses in the intestine. The mechanisms responsible for the induction of pathogenic T cell responses are still poorly defined, although the recent progress has highlighted the critical roles of commensal bacteria, the innate immune system, myeloid cells (dendritic cells (DC) and macrophages), TH17 cells and regulatory T cells (Tregs). These recent findings have brought up a new focus of investigation, including characterization of the key innate immune signaling pathways and their roles in the development of pathogenic T cell responses. In particular, analyses of TH17 responses in the intestine have elucidated both pathogenic and protective roles of cytokines produced by these cells in the development of colitis. Similarly, accumulating evidence indicates that different innate signaling pathways (for example, IL-23-driven, versus TGFb and IL-6-driven) may have differential roles in the generation of pathogenic versus non-pathogenic or protective Th17 responses. In this proposal, we will investigate the role of innate immune sensing pathways in the initiation of pathogenic T cell responses in the intestine. Specifically, we will investigate the role of IL-6, IL-1, and TGFb in the generation of TH1 and TH17 responses, and their role in development of colitis. We will also examine the role of different innate pathways that lead to the generation of TH17 responses in the intestine.