Innate immune response to bacterial flagellins

描述(申请人提供)：鞭毛细菌是人类常见的病原体，可引起许多重要疾病，包括伤寒和霍乱。在许多肠道细菌感染和炎症性肠病患者中，Flagellin是免疫反应的主要靶抗原。因此，了解鞭毛蛋白激活先天和获得性免疫反应的非凡能力，对于肠道感染疫苗和佐剂的翻译研究以及预防炎症性疾病的基础研究至关重要。 使用2年的ARRA资助，我们发现固有受体TLR5对于发展对鞭毛蛋白的强大T细胞反应是必不可少的，但这需要一个以前没有研究过的非传统信号通路。此外，我们现在已经开发出灵敏的体外和体内检测方法来监测鞭毛蛋白特异性的激活。 树突状细胞的T细胞反应。在这次续签申请中，我们建议在ARRA资助下完成的成功研究的基础上，继续研究TLR5在鞭毛蛋白特异性免疫发展中的作用。 这个子项目的具体目标是：目的1.研究TLR5下游的一个新的信号通路，以验证DC需要CLR和自噬通路的组件来激活鞭毛蛋白特异性T细胞的假设。目的2.特定目的2.检测肠道DC亚群激活鞭毛蛋白特异性T细胞的能力，验证CCR6+PP DC对鞭毛病原体的获得性免疫应答的假设。我们的初步数据描述了在体外和体内检测鞭毛特异性T细胞反应的最先进技术的发展。我们的总体假设是，TLR5作为肠道DC上的清道夫受体，将T细胞的反应集中在鞭毛蛋白上。

DESCRIPTION (provided by applicant): Flagellated bacteria are common pathogens of humans and cause many important diseases including typhoid and cholera. Flagellins are dominant target antigens of the immune response during many intestinal bacterial infections and also in patients suffering from inflammatory bowel disease. Understanding the extraordinary ability of flagellins to activate innate and adaptive immune responses is therefore of critical importance for translational research on vaccines and adjuvants for intestinal infections and for basic research on the prevention of inflammatory disease. Using 2-year ARRA funding, we have found that the innate receptor TLR5 is essential for the development of a robust T cell response to flagellin, but that this requires an unconventional signaling pathway that has not previously been examined. In addition, we have now developed sensitive in vitro and in vivo assays to monitor the activation of flagellin-specific T cell responses by dendritic cells. In this renewal application we propose to build upon our successful studies completed with ARRA funding and continue studying the role of TLR5 in the development of flagellin-specific immunity. The specific aims of this sub-project are: Aim 1. Examine a new signaling pathway downstream of TLR5 to test the hypothesis that components of CLR and autophagic pathways are required by DCs to activate flagellin-specific T cells. Aim 2. Specific Aim 2. Examine the ability of intestinal DC subsets to activate flagellin-specific T cells, to test the hypothesis tha CCR6+ PP DCs are responsible for adaptive immune responses to flagellated pathogens. Our preliminary data describe the development of state-of-the-art technology to examine flagellin- specific T cell responses in vitro and in vivo. Our overall hypothesis is that TLR5 functions as a scavenger receptor on intestinal DCs to focus T cell responses onto flagellin.