CD103 engagement regulates intestinal IEL effector function

项目摘要。 粘液监视肠道屏障的组织驻留淋巴细胞是至关重要的， 肠道病原体的入侵和保护性免疫的必要组成部分。单层上皮细胞 细胞排列在肠道中，在微生物、饮食抗原、毒素和 剩下的组织因此，淋巴细胞在肠屏障处的再活化必须紧密地 调节，因为过于强烈的反应可能导致上皮细胞的破坏，导致微生物 易位和最终的自身免疫，如在炎性肠病和乳糜泻中观察到的。 肠道中的组织驻留上皮内淋巴细胞（IEL）提供了抵御入侵的第一道防线。 微生物和肠道IEL室是由所谓的诱导和自然的 IELs。诱导的IEL是被募集到细胞中的CD 8ab + TCRab+组织驻留记忆（Trm IEL）细胞。 抗原暴露后的上皮区室。相比之下，天然IEL不受MHC限制，包括 表达TCRgd的CD 8aa + IEL（gd IEL）。gd和Trm IEL代表淋巴细胞中的大多数。 肠上皮细胞，可以起到保护和致病作用，但机制调节他们的 体内感染过程中的激活仍然在很大程度上未被探索。CD 103（aEb 7整联蛋白）由大多数人表达。 gd和Trm IEL位于肠道和其他屏障部位。CD 103结合上皮E-钙粘蛋白， 在组织淋巴细胞的募集和维持中起重要作用。然而， 感染期间肠内CD 103至IEL的功能尚未得到解决。成功完成 提出的目标将提供基本的深入了解的分子机制，CD 103连接 对E-钙粘蛋白的作用促进（1）Trm和（2）gd IEL的运动和激活，以及CD 103在 促进对肠道感染的保护性反应。这些研究将揭示新的机制， IEL和上皮细胞之间的直接相互作用有助于宿主免疫，并进一步定义了IEL的分子生物学特性。 在粘膜稳态和感染中调节前哨淋巴细胞群的线索。

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.