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

Washington University, Saint Louis MO

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Abstract

? 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.