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（由适用提供）：胃肠道是许多引起疾病的生物的进入点。肠壁非常薄，可最大程度地提高营养滥用，但也可以最大程度地减少病原体必须穿越才能进入。免疫细胞位于局部和远处部位，以监测源自肠子的感染。但是，必须严格调节免疫反应，以免导致组织损伤和自身免疫性。这是由肠叶轴，胃肠道和肝脏之间的通信来说明的。排干胃肠道的门静脉依赖于肠道的物质到肝脏监测抗原的肝脏，但也可能因无害分子而被激活。最近，我们的实验室确定了一种新型的天然杀伤（NK）细胞谱系，它限制在肝脏，CD49A的表达，转录因子依赖性和细胞因子产生中。肝居住的NK细胞锚定在正弦曲线中，在那里它们遇到通过门静脉进入的血液。这表明肝脏居住的NK细胞可以响应源自胃肠道的刺激性。为了确定在胃肠道感染期间，我们建议在用弓形虫Gondii感染的背景下研究这些细胞，这是一种细胞内寄生虫，口服并穿透肠上皮上皮。初步数据表明，腹膜内注射寄生虫后，CD49A+ DX5+ NK细胞出现在腹膜中。这些细胞与常规NK细胞不同，通过表达循环和组织居住的NK细胞的标记，而对抗生物小鼠的感染表明它们不是天然腹膜细胞。我们假设在T. gondii感染期间动员了肝脏居住的NK细胞并迁移到腹膜。在那里，它们可能有助于清除寄生虫或免疫响应的调节。我们的目标是确定确定腹膜CD49A+ DX5+ NK细胞的来源，它们的募集和激活机制以及它们的功能，以阐明对胃肠道感染的免疫反应的新机制。