The CXCR3(+)CD56Bright phenotype characterizes a distinct NK cell subset with anti-fibrotic potential that shows dys-regulated activity in hepatitis C.
BACKGROUND
In mouse models, natural killer (NK) cells have been shown to exert anti-fibrotic activity via killing of activated hepatic stellate cells (HSC). Chemokines and chemokine receptors critically modulate hepatic recruitment of NK cells. In hepatitis C, the chemokine receptor CXCR3 and its ligands have been shown to be associated with stage of fibrosis suggesting a role of these chemokines in HCV associated liver damage by yet incompletely understood mechanisms. Here, we analyzed phenotype and function of CXCR3 expressing NK cells in chronic hepatitis C.


METHODS
Circulating NK cells from HCV-infected patients (n = 57) and healthy controls (n = 27) were analyzed with respect to CXCR3 and co-expression of different maturation markers. Degranulation and interferon-γ secretion of CXCR3(+) and CXCR3(-) NK cell subsets were studied after co-incubation with primary human hepatic stellate cells (HSC). In addition, intra-hepatic frequency of CXCR3(+) NK cells was correlated with stage of liver fibrosis (n = 15).


RESULTS
We show that distinct NK cell subsets can be distinguished based on CXCR3 surface expression. In healthy controls CXCR3(+)CD56Bright NK cells displayed strongest activity against HSC. Chronic hepatitis C was associated with a significantly increased frequency of CXCR3(+)CD56Bright NK cells which showed impaired degranulation and impaired IFN-γ secretion in response to HSC. Of note, we observed intra-hepatic accumulation of this NK cell subset in advanced stages of liver fibrosis.


CONCLUSIONS
We show that distinct NK cell subsets can be distinguished based on CXCR3 surface expression. Intra-hepatic accumulation of the functionally impaired CXCR3(+)CD56Bright NK cell subset might be involved in HCV-induced liver fibrosis.
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Marianne
M
Eisenhardt
Andreas
A
Glässner
Benjamin
B
Krämer
Christian
C
Körner
Bernhard
B
Sibbing
Pavlos
P
Kokordelis
Hans Dieter
HD
Nischalke
Tilman
T
Sauerbruch
Ulrich
U
Spengler
Jacob
J
Nattermann
D000293:Adolescent; D000328:Adult; D000368:Aged; D019002:CD56 Antigen / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000378:metabolism; D006526:Hepatitis C / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D010641:Phenotype; D054367:Receptors, CXCR3 / Q000378:metabolism*; D055815:Young Adult
D019002:CD56 Antigen; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D054367:Receptors, CXCR3