Research ArticleImpaired CD4+ T cell stimulation of NK cell anti-fibrotic activity may contribute to accelerated liver fibrosis progression in HIV/HCV patients

Background & AimsHIV/HCV co-infection is characterized by a faster progression to liver fibrosis compared to HCV mono-infection. Epidemiologic studies found an association between low CD4+ T cell counts and advanced stages of liver fibrosis. However, the mechanisms underlying this association remain unclear.CD4+ T cells critically modulate NK cell activity. Of note, NK cells have been shown to display anti-fibrotic activity via killing of activated hepatic stellate cells (HSC). Thus, we speculated that CD4+ T cells might modulate fibrosis progression by interacting with NK cells.MethodsNK cells from HCV(+) (n = 35), HIV(+)/HCV(+) (n = 28), HIV(+) (n = 8) patients, and healthy controls (n = 30) were used in this study. NK cells were cultured in the presence or absence of supernatants from CD3/CD28-stimulated CD4+ cells. Then, NK cells were co-incubated with activated HSC and studied for degranulation, IFN-γ secretion, and induction of HSC apoptosis.ResultsFollowing incubation with CD4+ T cell supernatants, NK cells displayed a significantly increased activity against primary HSC as compared to unstimulated NK cells. This effect was, at least in part, mediated via an IL-2 dependent upregulation of NKG2D expression. HCV/HIV co-infection was associated with an impaired IL-2 secretion of CD4+ T cells resulting in an ineffective stimulation of anti-fibrotic NK cell function.ConclusionsHere, we show that CD4+ T cells are able to stimulate anti-fibrotic NK cell activity via IL-2 mediated upregulation of NKG2D. HIV-induced loss of CD4+ T cells together with an impaired activity of CD4+ T cells may contribute to accelerate progression of liver fibrosis observed in co-infection.