DEVELOPMENT AND FUNCTION OF INTESTINAL LYMPHOID TISSUES

描述（由申请人提供）：最近的研究确定了与粘膜表面相关的NK细胞亚群，或粘膜NK细胞。这些NK细胞显示出多种独特的特性，包括在促炎细胞因子的作用下产生IL-22来促进上皮修复和稳态，因此这些产生IL-22的NK细胞已被证明在改善肠道炎症中发挥重要作用。这些粘膜NK细胞是在炎症反应中产生的，其起源与传统NK细胞不同。此外，粘膜NK细胞具有类似于成人淋巴组织诱导剂（LTi）样细胞的表型，这些细胞负责形成孤立肠淋巴组织（淤泥），包括它们对转录因子ROR3t的发育依赖，以及它们在未发炎肠道的淤泥中居住。基于这些观察和我们的初步数据，我们假设在肠道炎症期间，淤泥中的成体LTi样细胞分化为粘膜NK细胞，随后在t淋巴细胞产生IL-21的反应下成熟，并重新分布到炎症上皮，产生IL-22以响应IL-23，介导上皮的修复和维持。在具体目标1中，我们将评估成人肠LTi样细胞向粘膜NK细胞和树突状细胞（DC）分化的能力，并评估促进粘膜NK细胞和DC发育的因素。在具体目标2中，我们将确定淤泥和肠道微生物群在粘膜NK细胞发育和粘膜NK细胞再分布到上皮的过程中的作用。在具体目标3中，我们将评估在粘膜NK细胞成熟、再分布和IL-22产生中发挥作用的因素/细胞类型。这些研究结果将显著增加我们对粘膜免疫系统如何促进炎症期间上皮屏障维护和修复的理解，并将为肠道慢性炎症性疾病的治疗开辟新的研究途径。

DESCRIPTION (provided by applicant): Recent studies identified a subset of NK cells associated with mucosal surfaces, or mucosal NK cells. These NK cells displayed multiple unique properties including the production of IL-22 to promote epithelial repair and homeostasis in response to proinflammatory cytokines, and accordingly these IL-22 producing NK cells have been demonstrated to play an important role in ameliorating intestinal inflammation. These mucosal NK cells are generated in response to inflammation and have an origin distinct from conventional NK cells. Moreover mucosal NK cells have a phenotype resembling the adult lymphoid tissue inducer (LTi) like cells that are responsible for the formation of solitary intestinal lymphoid tissues (SILT), including their developmental dependence upon the transcription factor ROR3t, and their residence within SILT in the uninflamed intestine. Based upon these observations and our preliminary data we hypothesize that during intestinal inflammation adult LTi like cells within the SILT differentiate into mucosal NK cells, subsequently mature in response to IL-21 produced by T-lymphocytes, and redistribute to the inflamed epithelium to produce IL-22 in response to IL-23 to mediate epithelial repair and maintenance. In specific aim 1 we will evaluate the ability of LTi like cells from the adult intestine to differentiate into mucosal NK cells and dendritic cells (DC) and evaluate the factors promoting mucosal NK cell and DC development. In specific aim 2 we will identify the role of SILT and luminal microbiota in the process of mucosal NK cell development and mucosal NK cell redistribution to the epithelium. In specific aim 3 we will evaluate the factors/cell types playing a role in mucosal NK cell maturation, redistribution, and IL-22 production. Findings from these studies will significantly increase our understanding of how the mucosal immune system facilitates epithelial barrier maintenance and repair during inflammation, and will open up new avenues of investigation for treatment of chronic inflammatory diseases of the intestine. PUBLIC HEALTH RELEVANCE: During intestinal inflammation a unique population of natural killer cells are generated. These cells produce cytokines promoting epithelial barrier maintenance and repair in response to inflammatory mediators. This proposal will investigate how these cells are generated and how they function to promote epithelial repair.