title: Impaired CD4⁺ T cell stimulation of NK cell anti-fibrotic activity may contribute to accelerated liver fibrosis progression in HIV/HCV patients.
abstract: OBJECTIVE
  HIV/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.
  
  
  METHODS
  NK 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.
  
  
  RESULTS
  Following 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.
  
  
  CONCLUSIONS
  Here, 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.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Glässner
authors.forename: Marianne
authors.initials: M
authors.lastname: Eisenhardt
authors.forename: Pavlos
authors.initials: P
authors.lastname: Kokordelis
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krämer
authors.forename: Franziska
authors.initials: F
authors.lastname: Wolter
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.forename: Christoph
authors.initials: C
authors.lastname: Boesecke
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Rockstroh
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018920:Coculture Techniques; D060085:Coinfection / Q000276:immunology* / Q000473:pathology; D017077:Culture Media, Conditioned; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000276:immunology*; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000473:pathology; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D017077:Culture Media, Conditioned; C508594:IL2 protein, human; D007376:Interleukin-2; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K
keywords: Apoptosis; CD4(+) T cells; FACS; FBS; HCV; HIV; HIV/HCV co-infection; HSC; Hepatic stellate cells; IFN; IL; IL-2; Liver fibrosis; NK cell; NK cells; NKG2D; PBMC; SIV; SteCM; TRAIL; fetal bovine serum; fluorescence-activated cell sorting; hepatic stellate cells; hepatitis C virus; human immunodeficiency virus; interferon; interleukin; natural killer cell; peripheral blood mononuclear cells; simian immunodeficiency virus; stellate cell medium; tumour necrosis factor related apoptosis inducing ligand