Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection.
Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection.
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DOI：
10.1371/journal.ppat.1001227
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发表时间：
2010-12-16
期刊：
影响因子：
6.7
通讯作者：
Maini MK
中科院分区：
文献类型：
--
作者：
Peppa D;Micco L;Javaid A;Kennedy PT;Schurich A;Dunn C;Pallant C;Ellis G;Khanna P;Dusheiko G;Gilson RJ;Maini MK
NK细胞富集于肝脏，约占肝内淋巴细胞的三分之一。我们之前已经证明，它们上调慢性乙型肝炎病毒感染（CHB）患者的死亡配体TRAIL，使它们能够杀死携带TRAIL受体的肝细胞。在这项研究中，我们研究了NK细胞除了其致病作用外，是否在慢性乙型肝炎中具有抗病毒潜力。我们对64名慢性乙型肝炎患者的NK细胞亚群和效应功能进行了表征，并与31名健康对照进行了比较。我们发现，与TRAIL表达上调和细胞溶解功能维持相反，NK细胞在CHB中产生IFN-γ的能力明显受损。这种NK细胞的功能分化可以通过暴露于免疫抑制细胞因子IL-10在体外重现，这是在活动性慢性乙型肝炎患者中诱导的。IL-10选择性抑制NK细胞IFN-γ的产生，而不改变细胞毒性或死亡配体的表达。强效抗病毒治疗减少了trail表达CD56bright NK细胞，这与抗病毒治疗诱导的肝脏炎症减少一致；然而，它不能使IL-10水平或NK细胞产生抗病毒细胞因子IFN-γ的能力正常化。阻断IL-10 +/−TGF-β可恢复慢性乙型肝炎患者外周和肝脏NK细胞产生IFN-γ的能力，从而增强其非溶细胞抗病毒能力。综上所述，慢性乙型肝炎患者NK细胞可能在免疫抑制细胞因子环境下处于部分功能耐受状态。它们产生抗病毒细胞因子IFN-γ的能力缺陷在接受抗病毒治疗的患者中持续存在，但可以通过IL-10+/−TGF-β阻断在体外得到纠正。乙型肝炎病毒（HBV）感染导致免疫介导的慢性肝损伤，每年造成100多万人死亡。自然杀伤（NK）细胞是肝脏中关键的免疫参与者之一，我们最近发现它可以引起HBV感染的肝脏损伤。在这里，我们研究了HBV感染肝脏中NK细胞的抗病毒潜力，并证明它们在产生细胞因子IFN-γ的能力上有特异性损伤，这可能限制它们控制HBV的能力。我们发现目前用于治疗HBV感染的强效抗病毒药物无法完全逆转这种NK细胞功能缺陷。我们确定了HBV免疫抑制细胞因子环境在下调NK细胞抗病毒功能中的作用，这种作用可以通过特异性阻断IL-10和TGF-β来恢复。因此，这项工作强调了导致慢性HBV感染免疫控制失败的机制，为新的治疗选择铺平了道路。
NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-γ in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-γ production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56bright NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-γ. Blockade of IL-10 +/− TGF-β restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-γ, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-γ persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/− TGF-β blockade. Hepatitis B virus (HBV) infection is responsible for more than a million deaths annually as a result of the immune-mediated chronic liver damage it induces. One of the key immune players in the liver is the natural killer (NK) cell, which we have recently found can cause liver damage in HBV infection. Here we address the antiviral potential of NK cells in the HBV-infected liver and demonstrate that they have a specific impairment in their ability to produce the cytokine IFN-γ, which could limit their capacity to control HBV. We find that the potent antiviral drugs currently being used to treat HBV infection are unable to fully reverse this NK cell functional defect. We define a role for the immunosuppressive cytokine environment in HBV in down-regulating NK cell antiviral function, which can be restored by specific blockade of IL-10 and TGF-β. This work therefore highlights a mechanism contributing to the failure of immune control in chronic HBV infection, paving the way to new therapeutic options.
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影响因子：
20.3
作者：
Fauriat, Cyril;Long, Eric O.;Bryceson, Yenan T.
通讯作者：
Bryceson, Yenan T.
DOI：
10.1084/jem.20061287
发表时间：
2007-03-19
期刊：
The Journal of experimental medicine
影响因子：
--
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Dunn C;Brunetto M;Reynolds G;Christophides T;Kennedy PT;Lampertico P;Das A;Lopes AR;Borrow P;Williams K;Humphreys E;Afford S;Adams DH;Bertoletti A;Maini MK
通讯作者：
Maini MK
影响因子：
20.3
作者：
Caraux, A;Kim, N;Colucci, F
通讯作者：
Colucci, F
影响因子：
32.4
作者：
Maroof, Asher;Beattie, Lynette;Zubairi, Soombul;Svensson, Mattias;Stager, Simona;Kaye, Paul M.
通讯作者：
Kaye, Paul M.
影响因子：
20.3
作者：
Coudert, JD;Zimmer, J;Held, W
通讯作者：
Held, W