Ribavirin to the Rescue: Natural Killer-Cell Function After Hepatitis C Virus Treatment in Liver Transplant Recipients.
Ribavirin to the Rescue: Natural Killer-Cell Function After Hepatitis C Virus Treatment in Liver Transplant Recipients.
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利巴韦林的救援：肝移植受者丙型肝炎病毒治疗后的自然杀伤细胞功能。
DOI：
10.1097/tp.0000000000003613
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发表时间：
2021
期刊：
影响因子：
6.2
通讯作者：
Calabrese,DanielR
中科院分区：
文献类型：
--
作者：
Calabrese,DanielR
虽然自然杀伤（NK）细胞因其细胞毒性的主要功能而得名，但它们也通过分泌干扰素(IFN)-γ和肿瘤坏死因子-α而成为有效的免疫招募者。与靶特异性依赖于基因重排的T细胞或B细胞不同，NK细胞的作用是由来自多种体细胞编码受体的激活或抑制信号的整合决定的。令人惊讶的是，在单个人类血液样本中已鉴定出bb30 000个个体nk细胞表型。在众多受体组合中，NK细胞将自身与缺失或受伤的自身区分开来的能力是其在实体器官移植结果中的核心作用。NK细胞一方面可以通过消除供体抗原呈递细胞和同种异体受体效应T细胞来促进同种异体移植物耐受，另一方面也可以通过抗体依赖细胞介导的细胞毒性和对缺血再灌注损伤过程中诱导的损伤分子的识别来促进急性和慢性同种异体移植物排斥反应。没有什么比慢性病毒感染和实体器官移植的融合更明显了。丙型肝炎病毒（HCV）感染的后遗症是肝移植的主要全球适应症。4肝损伤程度取决于宿主对HCV感染的免疫反应，感染控制取决于t细胞和nk细胞的有效功能。因此，慢性HCV抗原刺激导致t细胞能量和nk细胞受体库的扭曲。此外，持续暴露于内源性IFN-α会导致nk细胞功能的长期改变，其特征是细胞毒性增加和细胞因子产生能力降低（图1A）。虽然有研究表明慢性HCV感染中nk细胞表型偏斜，但尚不清楚在切除感染器官和免疫抑制的情况下，肝移植后是否会发生同样的现象。在这一期的《移植》杂志中，Adenugba等人报道，与未感染hcv的肝移植受者相比，hcv感染的肝移植受者具有相似的nk细胞功能偏转，CD107a（细胞毒性指标）增加，IFN-γ容量降低。作者证明，体外IFN-α刺激可在hcv感染的肝移植受体的NK细胞中复制改变的信号换能器和转录激活子（STAT）信号传导（图1B）。具体来说，在hcv感染肝移植受者的NK细胞中，相对于其他肝移植受者，STAT1和磷酸化的STAT1升高，磷酸化的STAT4降低。有趣的是，这种STAT4信号模式在所有肝移植受者的循环NK细胞中都有报道，与HCV状态和免疫抑制无关，这表明某种程度的IFN-γ能力减弱可能是耐受性的标志。虽然很明显NK细胞是肝移植后操作耐受的重要介质，但这种相互作用的机制尚未完全阐明。因此，了解如何将这些发现与临床结果联系起来仍然具有挑战性。值得注意的是，虽然肝移植中HCV感染被证明会改变外周血基因转录特征，但它不会改变与耐受性相关的13个nk细胞基因的转录，这表明HCV感染对nk细胞功能的影响可能与耐受性机制无关。在引入直接作用抗病毒药物（DAAs）之前，肝移植…
While natural killer (NK) cells earn their namesake through their primary function of cell cytotoxicity, they are also potent immune recruiters via secretion of interferon (IFN)-γ and tumor necrosis factor-α. In contrast to T or B cells, where target specificity is dependent upon genetic rearrangement, action of NK cells is determined by the integration of activating or inhibiting signals from a diverse repertoire of somatically encoded receptors. Astoundingly,> 30 000 individual NK-cell phenotypes have been identified within a single human blood sample. 1 Conserved across this multitude of receptor combinations, the ability to distinguish self from missing or injured self is central to the role of NK cells in solid organ transplantation outcomes. On the one hand, NK cells can promote allograft tolerance through elimination of donor antigen-presenting cells and alloreactive recipient effector T cells, and on the other hand, they can also promote acute and chronic allograft rejection through antibody-dependent cell-mediated cytotoxicity and recognition of damage molecules such as those induced during ischemia-reperfusion injury. 2 Nowhere is this balancing act more evident than with the convergence of chronic viral infection and solid organ transplantation. 3 Sequelae of hepatitis C virus (HCV) infection are leading global indications for liver transplantation. 4 The degree of hepatic injury is dependent on the host immune response to HCV infection, and infection control depends on effective T-cell and NK-cell function. Consequently, chronic HCV antigen stimulation results in T-cell anergy and skewing of the NK-cell receptor repertoire. Further, persistent exposure to endogenous IFN-α induces long-standing alterations in NK-cell function marked by increased cytotoxicity and reduced capacity for cytokine production (Figure 1A). 5 While studies showing skewed NK-cell phenotype in chronic HCV infection are well documented, it was not clear if the same phenomenon would happen after liver transplant in the context of removal of the infected organ and immunosuppression. In this issue of Transplantation, Adenugba et al6 report that HCV-infected liver transplant recipients had similarly skewed NK-cell function with increased CD107a, a measure of cytotoxicity, and reduced IFN-γ capacity compared with HCV-uninfected liver transplant recipients. The authors demonstrated that in vitro IFN-α stimulation reproduced altered signal transducer and activator of transcription (STAT) signaling in NK cells from HCV-infected liver transplant recipients (Figure 1B). Specifically, in NK cells from HCV-infected liver transplant recipients, STAT1 and phosphorylated STAT1 were increased and phosphorylated STAT4 was decreased relative to other liver transplant recipients. Interestingly, this pattern of STAT4 signaling has been reported in circulating NK cells from all liver transplant recipients irrespective of HCV status and immunosuppression, suggesting that some degree of blunted IFN-γ capacity may be a marker of tolerance. 7 While it is clear that NK cells are important mediators of operational tolerance after liver transplantation, the mechanism of this interaction has not been fully elucidated. Therefore, understanding how to contextualize these findings in terms of clinical outcomes remains challenging. Notably, while HCV infection in liver transplantation was shown to alter peripheral blood gene transcription signatures, it did not change the transcription of 13 NK-cell genes associated with tolerance, suggesting that the impact of HCV infection on NK-cell function may be independent of mechanisms of tolerance. 8Before the introduction of direct-acting antivirals (DAAs), liver transplant …