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

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• 作者：Andreas Gl?ssner ; Marianne Eisenhardt ; Pavlos Kokordelis ; Benjamin Kr?mer ; Franziska Wolter ; Hans Dieter Nischalke ; Christoph Boesecke ; Tilman Sauerbruch ; J¨¹rgen K. Rockstroh ; Ulrich Spengler ; Jacob Nattermann
• 关键词：HIV ; human immunodeficiency virus ; HCV ; hepatitis C virus ; IL ; interleukin ; NK cell ; natural killer cell ; HSC ; hepatic stellate cells ; TRAIL ; tumour necrosis factor related apoptosis inducing ligand ; SIV ; simian immunodeficiency virus ; SteCM ; stellate cel
• 刊名：Journal of Hepatology
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：59
• 期：3
• 页码：427-433
• 全文大小：846 K

文摘

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Background & Aims

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-¦Ã 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.