Mechanisms of gamma delta intraepithelial lymphocyte regulation of intestinal innate immunity

γδ上皮内淋巴细胞调节肠道先天免疫的机制

• 批准号: 8953798
• 负责人: Karen Leigh Edelblum
• 金额: $ 7.9万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8953798
• 关键词: Address; Affect; Asses; Bacteria; Bacterial Translocation; Biological Response Modifiers; Celiac Disease; Cell physiology; Cells; Disease; Enteral; Epithelial; Epithelial Cells; Epithelium; Exposure to; Extracellular Space; Foundations; Frequencies; Future; Goals; Health; Human; Immune response; Infection; Inflammatory; Inflammatory Bowel Diseases; Intestinal Diseases; Intestinal Mucosa; Intestines; Knowledge; Lateral; Lead; Location; Lymphocyte; Lymphocyte Function; Mediating; Mediator of activation protein; Mentored Research Scientist Development Award; Molecular; Mucous Membrane; Natural Immunity; Paracrine Communication; Pathogenesis; Patients; Peptides; Positioning Attribute; Predisposition; Production; Public Health; Regulation; Reporting; Research; Role; Salmonella; Salmonella infections; Salmonella typhimurium; Shapes; Systemic infection; T-Lymphocyte; Testing; Time; Villous; adaptive immunity; antimicrobial; base; cell motility; cell type; commensal microbes; enteric pathogen; graft vs host disease; innate immune function; innovation; insight; intraepithelial; migration; monolayer; novel strategies; occludin; pathogen; prevent; public health relevance; response; tool

 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.

 描述（由申请人提供）：γδ IEL 位于肠上皮单层内，这些细胞与肠腔非常接近，使得 γδ IEL 成为对肠道病原体的直接反应者。在缺乏 γδIEL 的情况下，共生细菌和肠道病原体的易位都会增强，这证明了 γδ IEL 桥接先天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 γδ IEL 之间发生的串扰来证明，以促进响应沙门氏菌感染而释放抗微生物因子。我曾报道过 γδ IEL 迁移 以occludin依赖性方式对绒毛上皮进行连续监测，并且这种运动足以限制鼠伤寒沙门氏菌易位；然而，γδ 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不清楚。在 K01 研究期间，我开发了评估和基因调节 γδ IEL/上皮相互作用以响应肠道病原体所需的工具。基于这些新方法，拟议的 R03 研究将开始确定 γδ IEL 及其与上皮细胞的相互作用促进立即先天免疫反应以防止细菌易位的细胞机制。我的中心假设是，γδIEL 迁移和随后的上皮相互作用对于立即产生参与先天免疫的可溶性介质是必要的。为了检验这个假设，我将首先确定 occludin 依赖性 γδ IEL 迁移对 γδ 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有助于 γδIEL 介导的针对细菌入侵的保护的细胞机制。这些研究将为 γδ 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。这些结果预计将成为未来研究 γδ IEL 如何介导对共生细菌的先天免疫反应或在 IBD 等肠道疾病中宿主病原体识别反应缺陷的情况下的基础。这可能会导致评估肠粘膜内 γδ IEL/上皮相互作用和功能的新策略，作为治疗疾病的手段。