Mechanisms of gamma delta intraepithelial lymphocyte regulation of intestinal innate immunity

 描述(申请人提供)：γδIEL位于肠上皮单分子层内，这些细胞靠近肠腔使γδIEL对Ac成为肠道病原体的直接反应者。在没有γδIEL的情况下，共生细菌和肠道病原体的易位都得到了增强，证明了γδIEL在先天性免疫和获得性免疫之间架起桥梁的独特能力。这种先天免疫功能体现在肠道上皮细胞和γδIEL之间的串扰，以促进抗微生物因子的释放，以应对沙门氏菌感染。我已经报告了γδIEL迁移 以封闭蛋白依赖的方式提供对绒毛上皮的持续监测，这种运动性足以限制鼠伤寒沙门氏菌的移位；然而，γδIL迁移和随后的上皮相互作用在激活天然免疫中的作用尚不清楚。在我的K01研究期间，我开发了必要的工具来评估和从基因上调节γδIEL/上皮细胞对肠道病原体的反应。在这些新方法的基础上，拟议的R03研究将开始确定γδIEL及其与上皮细胞的相互作用促进即时先天免疫反应以防止细菌易位的细胞机制(S)。我的中心假设是，γδIEL的迁移和随后的上皮相互作用对于参与先天免疫的可溶性介质的即时产生是必要的。为了验证这一假设，我将首先确定依赖阻滞素的γδIEL迁移对γδIEL和上皮细胞产生的要求 然后评估这些可溶性因子在γδIEL介导的抗细菌入侵保护中的细胞机制。这些研究将为γδIELs作为第一道防线的功能角色提供新的机械论见解 对抗流明病原体。这些结果有望成为未来研究γδIEL如何介导对共生细菌的先天性免疫反应，或在肠道疾病(如IBD)中有缺陷的宿主病原体识别反应的背景下的基础。这可能导致新的策略来评估γδIEL/上皮细胞的相互作用和肠粘膜内的功能，作为治疗疾病的手段。

 DESCRIPTION (provided by applicant): γδ IELs are located within the intestinal epithelial monolayer, and the close proximity of these cells to the intestinal lumen positions γδ IELs to ac as immediate responders to enteric pathogens. In the absence of γδIELs, translocation of both commensal bacteria and enteric pathogens is enhanced, demonstrating the unique ability of γδ IELs to bridge innate and adaptive immunity. This innate immune function is demonstrated by the crosstalk that occurs between intestinal epithelial cells and γδ IELs to promote the release f anti-microbial factors in response to Salmonella infection. I have reported that γδ IEL migration provides continuous surveillance of the villous epithelium in an occludin-dependent manner and that this motility is sufficient to limit S. typhimurium translocation; however, the role of γδ IL migration and subsequent epithelial interactions in the activation of innate immunity remains unknown. During my K01 studies, I developed the tools necessary to assess and genetically modulate γδ IEL/epithelial interactions in response to an enteric pathogen. Building on these novel approaches, the proposed R03 studies will begin to identify the cellular mechanism(s) by which γδ IELs and their interactions with epithelial cells promote an immediate innate immune response to prevent bacterial translocation. My central hypothesis is that γδIEL migration and subsequent epithelial interactions are necessary for the immediate production of soluble mediators involved in innate immunity. To test this hypothesis, I will first determine the requirement for occludin-dependent γδ IEL migration on γδ IEL and epithelial cell production of soluble immune mediators and then assess the cellular mechanisms by which these soluble factors contribute to γδIEL-mediated protection against bacterial invasion. These studies will provide new mechanistic insights into the functional role of γδ IELs as the first line of defense against luminal pathogens. The results are expected to serve as the foundation for future study of how γδ IELs mediate an innate immune response to commensal bacteria or in the context of defective host pathogen recognition responses in intestinal diseases such as IBD. This may lead to new strategies to assess γδ IEL/epithelial interactions and function within the intestina mucosa as means to treat disease.