Natural killer cell subsets in the liver: phenotype, function and role in obesity-induced liver disease. (360G-Wellcome-105677_Z_14_Z)

Organ-specific natural killer (NK) cells form a distinct lineage from their circulating counterparts and have specialist physiological functions. In the last year, a liver-specific NK subset has been identified in mice. Whether an equivalent population exists in human liver is not yet known, nor is the function of these cells known in either humans or mice. My goal is to address these questions with specific reference to NASH. I will examine liver transplant perfusates by flow cytometry for the transcription factors that define the liver-specific NK subset, and for relevant surface markers. I will then investigate whether any of the subsets identified are liver-specific using in vitro lymphocyte differentiation assays and by comparing their representation in donor- versus recipient-derived NK cells from explanted livers. I will perform ex vivo assays for expected functions such as cytokine production and cytotoxicity. Microarray analysis will also be used to identify any novel function s. Using marginal tissue from liver resections, I will determine whether NK subset frequency and function differs between NASH livers and controls. To test the hypothesis that liver-specific NK cells affect the progression of NASH, I will examine disease severity in Tbx21[fl/fl]Ncr1[icre] mice, which specifically lack these cells.