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（由应用提供）：γδIEL位于肠上皮单层内，这些细胞与肠腔腔位置的近距离接近AC作为促进病原体的直接响应者。在没有γδIEL的情况下，共生细菌和促进病原体的转运得到了增强，这表明γδIELS桥接了先天和适应性免疫组织化学物质的独特能力。这种先天的免疫组织化学函数通过肠上皮细胞和γδIEL之间发生的串扰证明了这种杂交，以促进响应沙门氏菌感染的释放f抗微生物因子。我报道γδIEL迁移 以闭合依赖性方式提供对绒毛上皮的连续监视，并且这种运动足以限制鼠伤寒链霉菌的易位。然而，γδIL迁移和随后的上皮相互作用在先天免疫激活中的作用尚不清楚。在我的K01研究中，我开发了评估和一般调节γδIEL/上皮相互作用所必需的工具，以响应肠病原体。在这些新型方法的基础上，提出的R03研究将开始鉴定γδIELS及其与上皮细胞相互作用的细胞机制，从而促进了立即的先天免疫反应，以防止细菌易位。我的中心假设是，对于立即生产与先天免疫的固体介体有关的γδIEL迁移和随后的上皮相互作用是必需的。为了检验这一假设，我将首先确定依赖闭塞的γδIEL在γδIEL和上皮细胞产生上的要求 可溶性免疫介质，然后评估这些固体因子有助于γδEIL介导的对细菌侵袭的保护的细胞机制。这些研究将为γδiels作为第一道防线的功能作用提供新的机械见解 针对腔病原体。预计该结果将成为未来研究γδ如何介导对共生细菌的先天免疫反应的基础，或者在肠道疾病（例如IBD）中的宿主病原体识别反应中有缺陷的基础。这可能会导致新的策略评估肠粘膜中γδIEL/上皮相互作用和功能作为治疗疾病的手段。