CD103 engagement regulates intestinal IEL effector function

CD103 参与调节肠道 IEL 效应器功能

基本信息

批准号：
10676560
负责人：
Tessa Bergsbaken
金额：
$ 66.02万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-10 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676560
关键词：
Address Antigens Autoimmunity Behavior Binding Biological Process CD8B1 gene Carcinoma Celiac Disease Cell Line Cell physiology Cells Colorectal Communicable Diseases Cues Cytoplasmic Granules E-Cadherin Epithelial Cells Epithelium Event Exhibits Exocytosis Gene Expression Goals Granzyme Homeostasis Immune System Diseases Immune system Immunity Infection Infection Control Inflammatory Bowel Diseases Integrins Intestines Invaded Investigation Knowledge Ligation Lymphocyte Lymphocyte Activation Lymphocyte Count Lymphocyte Function Maintenance Mediating Memory Microbe Mission Modeling Molecular Mucous Membrane National Institute of Allergy and Infectious Disease Pathogenicity Play Population Public Health Regulation Research Rest Role Sentinel Signal Pathway Signal Transduction Site T-Lymphocyte Therapeutic Tissues Toxin Tumor-Infiltrating Lymphocytes United States National Institutes of Health Virus Diseases Work cadherin 10 cell motility combinatorial cytokine dietary enteric infection enteric pathogen experimental study human disease improved outcome in vivo insight intestinal barrier intestinal epithelium intestinal homeostasis intraepithelial microbial microorganism migration novel pathogen prevent recruit response

项目摘要

PROJECT SUMMARY. Mucosal surveillance of the intestinal barrier by tissue-resident lymphocytes is critical for preventing the invasion of enteric pathogens and a necessary component of protective immunity. A single layer of epithelial cells lines the intestinal tract and provides a physical barrier between microbes, dietary antigens, toxins and the rest of the tissue. Therefore, the reactivation of lymphocytes at the intestinal barrier must be tightly regulated, as too robust of a response could result in destruction of the epithelium leading to microbial translocation and eventual autoimmunity, as observed in inflammatory bowel disease and celiac disease. Tissue-resident intraepithelial lymphocytes (IELs) in the intestine provide a first line of defense against invading microorganisms and the intestinal IEL compartment is composed of what has been termed induced and natural IELs. Induced IELs are CD8ab+ TCRab+ tissue resident memory (Trm IELs) cells that are recruited to the epithelial compartment following antigen exposure. In contrast, natural IELs are not MHC-restricted and include CD8aa+ IELs expressing TCRgd (gd IELs). gd and Trm IELs represent the majority of the lymphocytes in the intestinal epithelium and could serve both protective and pathogenic roles, yet mechanisms regulating their activation during infection in vivo remain largely unexplored. CD103 (aEb7 integrin) is expressed by the majority of gd and Trm IELs located in the intestine and at other barrier sites. CD103 binds to epithelial E-cadherin and plays an important role in the recruitment and maintenance of tissue lymphocytes. However, the contribution of CD103 to IEL functionality within the intestine during infection has not been addressed. Successful completion of the proposed aims will provide fundamental insight into the molecular mechanisms by which CD103 ligation to E-cadherin promotes (1) the motility and activation of Trm and (2) gd IELs and the role of CD103 in promoting protective responses to enteric infection. These studies will uncover novel mechanisms by which direct interaction between IELs and epithelial cells contribute to host immunity and further define the molecular cues regulating sentinel lymphocyte populations in mucosal homeostasis and infection.

项目摘要。通过组织居民淋巴细胞对肠道屏障的粘膜监测对于防止入侵肠道病原体和保护性免疫的必要组成部分。一层上皮细胞在肠道上排成一条肠道，并在微生物，饮食抗原，毒素和其余的组织。因此，必须紧密地在肠屏障处的淋巴细胞重新激活受调节，由于反应太强大可能会导致上皮破坏导致微生物如在炎症性肠病和腹腔疾病中所观察到的，易位和最终自身免疫性。肠内的组织内淋巴细胞（IEL）提供了针对入侵的第一道防御微生物和肠道IEL室由所谓的诱导和自然组成 IELS。诱导的IEL是招募到抗原暴露后的上皮室。相比之下，天然IEL不受MHC的限制，包括 CD8AA+ IEL表达TCRGD（GD IELS）。 GD和TRM IEL代表大多数淋巴细胞肠上皮，可以发挥保护性和致病作用，但调节其机制体内感染期间的激活在很大程度上仍未开发。 CD103（AEB7整合素）由多数表达 GD和TRM IEL位于肠和其他屏障站点。 CD103与上皮E-钙粘蛋白和在组织淋巴细胞的募集和维持中起着重要作用。但是，尚未解决感染过程中肠内IEL功能的CD103。成功完成拟议的目标将提供对CD103结扎的分子机制的基本见解到E-钙粘蛋白促进（1）TRM和（2）GD IELS的运动和激活以及CD103在促进对肠道感染的保护性反应。这些研究将发现新的机制 IELS和上皮细胞之间的直接相互作用有助于宿主免疫，并进一步定义分子提示在粘膜稳态和感染中调节前哨淋巴细胞种群。