TLRs in Host Commensal Interactions

描述(申请人提供)：炎症性肠病的特点是肠道免疫反应紊乱。尽管最近的进展强调了共生细菌、天然免疫系统、髓系细胞(树突状细胞和巨噬细胞)、TH17细胞和调节性T细胞(Tregs)的关键作用，但诱导致病T细胞应答的机制仍不清楚。这些最新的发现带来了一个新的研究重点，包括关键的先天性免疫信号通路的特征及其在致病性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驱动的，而不是TGFb和IL-6驱动的)在致病性和非致病性或保护性Th17反应的产生中可能具有不同的作用。在这项建议中，我们将研究先天免疫感知通路在肠道致病T细胞反应启动中的作用。具体地说，我们将研究IL-6、IL-1和TGFb在TH1和TH17反应的产生中的作用，以及它们在结肠炎发展中的作用。我们还将研究不同的先天途径在肠道中产生TH17反应的作用。

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.