Mechanisms of gamma delta intraepithelial lymphocyte regulation of intestinal innate immunity

 描述（由申请方提供）：γ δ IEL位于肠上皮单层内，这些细胞与肠腔的紧密接近使γ δ IEL成为对肠道病原体的即时应答者。在不存在γ δ IEL的情况下，肠道细菌和肠道病原体的易位都得到增强，证明了γ δ IEL桥接先天性免疫和适应性免疫的独特能力。这种先天免疫功能通过肠上皮细胞和γ δ IEL之间发生的串扰来证明，以促进响应沙门氏菌感染的抗微生物因子的释放。我曾报道γ δ IEL迁移 以occludin依赖的方式提供绒毛上皮的连续监视，并且这种运动足以限制S。鼠伤寒沙门氏菌易位;然而，γ δ IL迁移和随后的上皮相互作用在先天免疫激活中的作用仍然未知。在我的K01研究期间，我开发了必要的工具来评估和遗传调节γ δ IEL/上皮相互作用以响应肠道病原体。在这些新方法的基础上，拟议的R03研究将开始确定γ δ IEL及其与上皮细胞的相互作用促进立即先天免疫应答以防止细菌移位的细胞机制。我的中心假设是，γ δ IEL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立即产生是必要的。为了验证这一假设，我将首先确定闭合蛋白依赖性γ δ IEL迁移对γ δ IEL和上皮细胞产生 可溶性免疫介质，然后评估这些可溶性因子促进γ δ IEL介导的针对细菌入侵的保护作用的细胞机制。这些研究将为γ δ IEL作为第一道防线的功能作用提供新的机制见解 对抗管腔病原体。这些结果有望成为未来研究γ δ IEL如何介导对肠道细菌的先天免疫应答或在肠道疾病（如IBD）中有缺陷的宿主病原体识别应答的背景下的基础。这可能会导致新的策略，以评估γ δ IEL/上皮细胞的相互作用和功能，作为手段，以治疗疾病的粘膜。

 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.