Impaired CD4+ T cell stimulation of NK cell anti-fibrotic activity may contribute to accelerated liver fibrosis progression in HIV/HCV patients
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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DOI：
10.1016/j.jhep.2013.04.029
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发表时间：
2013-09-01
影响因子：
25.7
通讯作者：
Nattermann, Jacob
中科院分区：
文献类型：
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作者：
Glaessner, Andreas;Eisenhardt, Marianne;Nattermann, Jacob
背景与目的：与HCV单一感染相比，HIV/HCV合并感染的特点是更快地进展为肝纤维化。流行病学研究发现，低CD 4（+）T细胞计数和肝纤维化的晚期之间存在关联。然而，这种关联的机制尚不清楚。CD 4（+）T细胞对NK细胞活性起着关键性的调节作用。值得注意的是，NK细胞已显示出通过杀死活化的肝星状细胞（HSC）而显示出抗纤维化活性。方法：收集HCV（+）患者（n = 35）、HIV（+）/HCV（+）患者（n = 28）、HIV（+）患者（n = 8）和健康对照者（n = 30）的NK细胞，用免疫组化方法检测NK细胞的表达。在存在或不存在来自⑶ 3/⑶ 28刺激的⑶ 4（+）细胞的上清液的情况下培养NK细胞。结果：NK细胞与CD 4（+）T细胞培养上清共孵育后，与未受刺激的NK细胞相比，对原代HSC的杀伤活性显著增强。该效应至少部分通过NKG 2D表达的IL-2依赖性上调介导。HCV/HIV共感染与CD 4（+）T细胞的IL-2分泌受损相关，导致抗纤维化NK细胞功能的无效刺激。结论：在这里，我们表明CD 4（+）T细胞能够通过IL-2介导的NKG 2D上调来刺激抗纤维化NK细胞活性。HIV诱导的CD 4（+）T细胞的损失以及CD 4 + T细胞活性受损可能有助于加速在合并感染中观察到的肝纤维化进展。(c)2013年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
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-gamma 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. (c) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.