Impaired CD4+ T cell-mediated stimulation of NK cell anti-fibrotic activity may contribute to accelerated progression towards HCV-associated liver fibrosis in HIV/HCV co-Infected patients
A. Glässner*, M. Eisenhardt, B. Krämer, F. Wolter, P. Kokordelis, B. Sibbing, H.D. Nischalke, J. Rockstroh, T. Sauerbruch, U. Spengler, J. Nattermann
Department of Internal Medicine I, University of Bonn, Bonn, Germany. *email@example.com
Chronic hepatitis C is a leading cause of liver fibrosis. HCV infection in
HIV-positive patients is characterized by a more rapid progression towards
liver fibrosis/cirrhosis as compared to individuals with HCV mono-infection.
NK cells have been shown to display
anti-fibrotic activity via killing of activated hepatic stellate cells (HSC).
Function of NK cells is regulated by both, soluble factors and cross-talk with
other immunocompetent cells.
Gradual loss of CD4+ T
cells is a hallmark of HIV infection.
Here, we analyzed the impact of CD4+ T cells on NK cell
total of 60 individuals (HCV(+), n=24; HIV(+)/HCV(+), n=20; healthy controls,
n=16) were enrolled into this study.
Purified NK cells were cultured in
the presence or absence of supernatants from CD3/CD28-stimulated CD4+
T cells and than co-incubated with activated primary human HSC (ScienCell)
followed by flowcytometric analysis of HSC apoptosis (detection of active
caspase-3), NK cell degranulation (CD107a), and IFN-g secretion.
Following incubation with supernatants from CD4+ T cells obtained
from healthy controls, NK cells displayed a significantly increased activity
against primary HSC as compared to unstimulated NK cells with higher CD107a
expression (3.8 ±0.8% vs. 19.2 ±1.9%;
p< 0.05) and IFN-γ secretion (0.3 ±0.1% vs. 7.4 ±1.1%; p< 0.05). Moreover, we found a
significant increase in NK cell-induced HSC apoptosis (6.1
±1% vs. 46.1 ±4.7%). Blocking experiments suggested an IL-2 mediated
Anti-HSC activity of NK cells was
positively correlated to the number of CD4+ T cells used in the experiments.
Of note, supernatants of equivalent
numbers of CD4+ T cells from HIV/HCV patients but not from HCV
mono-infected patients displayed a significantly reduced ability to trigger
anti-HSC activity of NK cells. Accordingly, we found that NK cells from HIV/HCV
patients showed a significantly lower ex
vivo activity against activated HSC as compared to NK cells from HCV
mono-infected patients (10.4 ±1.5% vs. 17.4 ±1.8%; p=0.006).
CD4+ T cells can trigger anti-fibrotic NK cell activity via an IL-2
mediated mechanism. Both, HIV-induced loss of CD4+ T cells and
impaired IL-2 secretion, may contribute to accelerated progression of liver
fibrosis in HIV/HCV infected patients.