Identifying the Function and Origin of Peritoneal NK Cells in T Gondii Infection

鉴定腹膜 NK 细胞在弓形虫感染中的功能和起源

• 批准号: 9223571
• 负责人: Eugene Park
• 金额: $ 3.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223571
• 关键词: Acute; Adoptive Transfer; Affect; Antigens; Autoimmunity; Blood; CXCR3 gene; Cell Lineage; Cells; Communication; Congenic Mice; Data; Dendritic Cells; Dependence; Development; Discontinuous Capillary; Disease; Distant; Environment; Epithelial Cells; Gastrointestinal tract structure; Hepatitis; Human; Immune; Immune response; Immune system; Impairment; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory Bowel Diseases; Interferon Type II; Intestinal parasite; Intestines; Intraperitoneal Injections; Ligation; Light; Liver; Mediating; Monitor; Mouse Strains; Mus; Natural Killer Cells; Oral; Organism; Outcome; Parasites; Pathology; Penetration; Peritoneal; Peritoneum; Play; Population; Portal vein structure; Positioning Attribute; Predisposition; Production; Recruitment Activity; Reporting; Residencies; Resistance; Role; Signal Transduction; Site; Sorting - Cell Movement; Source; Stimulus; TNF gene; Testing; Thinness; Tissues; Toll-like receptor 11; Toxoplasma gondii; Toxoplasmosis; Venous; combat; cytokine; experimental study; gastrointestinal infection; immunoregulation; inflammatory milieu; intestinal epithelium; intestinal homeostasis; monocyte; novel; nutrient absorption; pathogen; public health relevance; response; transcription factor

 DESCRIPTION (provided by applicant): That gastrointestinal tract is the point of entry for many disease-causing organisms. The intestinal wall is very thin, which maximizes absorption of nutrients but also minimizes the distance pathogens must traverse to gain entry. Immune cells are positioned at both local and distant sites to monitor for infection originating from the intestine. However, immune responses must be tightly regulated so as to not result in tissue damage and autoimmunity. This is illustrated by the gut-liver axis, a communication between the gastrointestinal tract and the liver. The portal vein, which drains the gastrointestinal tract, relys substances from the gut to the liver where immune cells monitor for antigens but can also become activated against innocuous molecules. Recently, our lab identified a novel lineage of natural killer (NK) cells, peculiar in its restriction to the liver, expression of CD49a, transcripion factor dependence, and cytokine production. Liver-resident NK cells are anchored in the sinusoids, where they encounter blood that enters through the portal vein. This suggests that liver-resident NK cells can respond to stimuli originating from the gastrointestinal tract. To determine if liver- resident NK cells play a role during gastrointestinal infection, we propose to study these cells in the context of infection with Toxoplasma gondii, an intracellular parasite tha spreads orally and penetrates the intestinal epithelium. Preliminary data show that following intraperitoneal injection of parasites, CD49a+DX5+ NK cells appear in the peritoneum. These cells differ from conventional NK cells by expressing markers of both circulating and tissue-resident NK cells, and infection of parabiotic mice reveals that they are not native peritoneal cells. We hypothesize that liver-resident NK cells are mobilized during T. gondii infection and migrate to the peritoneum. There, they may contribute to clearance of the parasite or regulation of the immune response. We aim to definitively determine the source of peritoneal CD49a+DX5+ NK cells, their mechanisms of recruitment and activation, and their function in order to elucidate novel mechanisms of immune response to gastrointestinal infection.

 描述（由申请人提供）：胃肠道是许多致病微生物的进入点。肠壁非常薄，这最大限度地吸收了营养物质，但也最大限度地减少了病原体必须穿越才能进入的距离。免疫细胞被定位在本地和远程站点，以监测来自肠道的感染。然而，必须严格调节免疫反应，以免导致组织损伤和自身免疫。这是由肠道-肝脏轴，胃肠道和肝脏之间的沟通说明。排出胃肠道的门静脉将物质从肠道输送到肝脏，在肝脏中免疫细胞监测抗原，但也可以被激活以对抗无害分子。最近，我们的实验室鉴定了一种新的自然杀伤（NK）细胞谱系，其独特之处在于其对肝脏的限制，CD 49 a的表达，转录因子依赖性和细胞因子的产生。肝脏NK细胞固定在血窦中，在那里它们遇到通过门静脉进入的血液。这表明，肝脏驻留NK细胞可以响应来自胃肠道的刺激。为了确定肝脏驻留NK细胞是否在胃肠道感染中发挥作用，我们建议在感染弓形虫的背景下研究这些细胞，弓形虫是一种经口传播并穿透肠上皮的细胞内寄生虫。初步数据显示，腹膜内注射寄生虫后，CD 49 a + DX 5 + NK细胞出现在腹膜中。这些细胞与传统的NK细胞不同，表达循环和组织驻留NK细胞的标志物，并且对联体小鼠的感染表明它们不是天然的腹膜细胞。我们推测，肝脏中的NK细胞在T。弓形虫感染并迁移至腹膜。在那里，它们可能有助于清除寄生虫或调节免疫反应。我们的目的是明确确定腹膜CD 49 a + DX 5 + NK细胞的来源，其募集和激活机制，以及它们的功能，以阐明胃肠道感染免疫应答的新机制。