title: Chronic HCV infection affects the NK cell phenotype in the blood more than in the liver.
abstract: Although epidemiological and functional studies have implicated NK cells in protection and early clearance of HCV, the mechanism by which they may contribute to viral control is poorly understood, particularly at the site of infection, the liver. We hypothesized that a unique immunophenotypic/functional NK cell signature exists in the liver that may provide insights into the contribution of NK cells to viral control. Intrahepatic and blood NK cells were profiled from chronically infected HCV-positive and HCV-negative individuals. Baseline expression of activating and inhibitory receptors was assessed, as well as functional responses following stimulation through classic NK cell pathways. Independent of HCV infection, the liver was enriched for the immunoregulatory CD56(bright) NK cell population, which produced less IFNγ and CD107a but comparable levels of MIP1β, and was immunophenotypically distinct from their blood counterparts. This profile was mostly unaltered in chronic HCV infection, though different expression levels of NKp46 and NKG2D were associated with different grades of fibrosis. In contrast to the liver, chronic HCV infection associated with an enrichment of CD161(low)perforin(high) NK cells in the blood correlated with increased AST and 2B4 expression. However, the association of relatively discrete changes in the NK cell phenotype in the liver with the fibrosis stage nevertheless suggests an important role for the NK response. Overall these data suggest that tissue localization has a more pervasive effect on NK cells than the presence of chronic viral infection, during which these cells might be mostly attuned to limiting immunopathology. It will be important to characterize NK cells during early HCV infection, when they should have a critical role in limiting infection.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Cormac
authors.initials: C
authors.lastname: Cosgrove
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Berger
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, United States of America; Medical Department 3, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Kroy
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Cheney
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Musie
authors.initials: M
authors.lastname: Ghebremichael
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jasneet
authors.initials: J
authors.lastname: Aneja
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Tomlinson
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Arthur Y
authors.initials: AY
authors.lastname: Kim
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Georg M
authors.initials: GM
authors.lastname: Lauer
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
mesh_terms: D000368:Aged; D019002:CD56 Antigen / Q000378:metabolism*; D005260:Female; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000473:pathology* / Q000821:virology; D008103:Liver Cirrhosis / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D054353:Perforin / Q000378:metabolism; D010641:Phenotype
chemical_list: D019002:CD56 Antigen; C527203:KLRB1 protein, human; C527085:KLRK1 protein, human; C522918:NCAM1 protein, human; C112260:NCR1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D054353:Perforin