LT-CD4+ cell modulation of natural killer cells is not compromised in hepatitis C/human immunodeficiency virus-coinfected patients with advanced liver fibrosis

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Background: It has been widely reported that natural killer (NK) cells ameliorates liver fibrosis by inducing cytostasis and apoptosis of hepatic stellate cells. We have previously demonstrated that hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-coinfected patients with advanced liver fibrosis show lower percentage of NK cells than individuals with low to mild fibrosis and healthy donors. Additionally, the cytotoxic activity of these cells is significantly reduced. Since LT-CD4 + modulate the function of NK cells, the aim of this work was to evaluate LT-CD4 + cell regulation of NK cell activation in HCV/HIV coinfected patients with different stages of liver fibrosis. Methods & Materials: Isolated LT-CD4 + cells from 18 HCV/HIV coinfected individuals (9 METAVIR F0-F1, 9 METAVIR F4) were activated with anti-CD3/CD28 beads for 2 days, and supernatants were collected. LT-CD4 + cell activation was studied by measuring CD69, CD25 and CD38 expression by flow cytometry (FC). Next, activated LT-CD4 + cell-conditioned media (CM) were used at two different dilutions to stimulate purified NK cells from healthy donors. After stimulation, these cells were exposed to the target cell line K562, and degranulation was examined by FC, measuring LAMP1/CD107a externalization. Results: Regarding LT-CD4 + cell activation, we did not find any differences in the expression of the activation markers CD25, CD69 or CD38 between T cells from patients with minimal and severe fibrosis (80.80 vs. 80.65%, 83.80 vs. 84.75% and 62.25 vs. 58.95%, respectively). Moreover, degranulation of NK cells was not differentially modulated by CM of ex-vivo stimulated LT-CD4 + from patients with low or advanced fibrosis, at any tested dilution (p > 0.05; Mann-Whitney test). After K562 challenge, the percentage of NK/CD107a + cells reached to 21.60%. When exposed to CM from patients with minimal or advanced fibrosis, the percentages increased to 38.30 and 35.50%, respectively (1:10 dilution), and to 62.20 and 61.30% with undiluted CM. Conclusion: Our results indicate that LT-CD4 + cell modulation of NK function is not compromised in HCV/HIV patients with advanced fibrosis. Therefore, in these individuals, impaired NK cell-mediated cytotoxicity may be related to a lower NK cell count and/or altered phenotype, rather than to a deficient LT-CD4 + cell stimulation.

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