Background & Aims

Chronic hepatitis affects phenotypes of innate and adaptive immune cells. Mucosal-associated invariant T (MAIT) cells are enriched in the liver as compared with the blood, respond to intra-hepatic cytokines, and (via the semi-invariant T-cell receptor) to bacteria translocated from the gut. Little is known about the role of MAIT cells in livers of patients with chronic hepatitis C virus (HCV) infection and their fate after antiviral therapy.

Methods

We collected blood samples from 42 patients with chronic HCV infection who achieved a sustained virologic response after 12 weeks of treatment with sofosbuvir and velpatasvir. Mononuclear cells were isolated from blood before treatment, at weeks 4 and 12 during treatment, and 24 weeks after the end of treatment. Liver biopsies were collected from 37 of the patients prior to and at week 4 of treatment. Mononuclear cells from 56 blood donors and 10 livers that were not suitable for transplantation were used as controls. Liver samples were assessed histologically for inflammation and fibrosis. Mononuclear cells from liver and blood were studied by flow cytometry and analyzed for responses to cytokine and bacterial stimulation.

Results

The frequency of MAIT cells among T cells was significantly lower in blood and liver samples of patients with HCV infection than of controls (median, 1.31% vs 2.32% for blood samples, P = .0048; and median, 4.34% vs 13.40% for liver samples, P = .001). There was an inverse correlation between the frequency of MAIT cells in the liver and histologically determined levels of liver inflammation (r = -.5437, P = .0006) and fibrosis (r = -.5829, P = .0002). MAIT cells from the liver had higher levels of activation and cytotoxicity than MAIT cells from blood (P < .0001). Production of interferon gamma by MAIT cells was dependent on monocyte-derived interleukin 18, and was reduced in patients with HCV infection in response to T-cell receptor-mediated but not cytokine-mediated stimulation, as compared with controls. Anti-viral therapy rapidly decreased liver inflammation and MAIT cell activation and cytotoxicity, and increased the MAIT cell frequency among intra-hepatic but not blood T cells. The MAIT cell response to T-cell receptor-mediated stimulation did not change during the 12 weeks of antiviral therapy.

Conclusions

In analyses of paired blood and liver samples from patients with chronic HCV infection before, during, and after antiviral therapy with sofosbuvir and velpatasvir, we found that intrahepatic MAIT cells are activated by monocyte-derived cytokines and depleted in HCV-induced liver inflammation.

中文翻译：

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丙型肝炎病毒引起的肝炎中黏膜相关不变T细胞的肝内消耗

背景与目标

慢性肝炎影响先天性和适应性免疫细胞的表型。与血液相比，与粘膜相关的不变T（MAIT）细胞在肝脏中富集，对肝内细胞因子作出反应，并且（通过半不变T细胞受体）对从肠道转移的细菌产生反应。关于MAIT细胞在慢性丙型肝炎病毒（HCV）感染患者的肝脏中的作用及其抗病毒治疗后的命运知之甚少。

方法

我们收集了42例慢性HCV感染患者的血液样本，这些患者在用sofosbuvir和velpatasvir治疗12周后获得了持续的病毒学应答。在治疗前，治疗期间第4和12周以及治疗结束后24周从血液中分离出单核细胞。在治疗前和治疗第4周时从37名患者中收集了肝活检。将来自56个不适合移植的献血者和10个肝脏的单核细胞用作对照。从组织学上评估肝脏样品的炎症和纤维化。通过流式细胞术研究了来自肝脏和血液的单核细胞，并分析了对细胞因子和细菌刺激的反应。

结果

HCV感染患者的血液和肝样本中T细胞中MAIT细胞的频率显着低于对照组（中位数，血液样本为1.31％vs 2.32％，P = .0048；中位数为4.34％vs 13.40％肝样本，P  = 0.001）。肝脏中MAIT细胞的频率与组织学确定的肝脏炎症水平（r =- 。 5437，P = .0006）和纤维化（r =- 。 5829，P = .0002）之间呈负相关。来自肝脏的MAIT细胞比来自血液的MAIT细胞具有更高水平的活化和细胞毒性（P<.0001）。与对照组相比，MAIT细胞产生的干扰素γ依赖于单核细胞衍生的白介素18，在HCV感染的患者中，T细胞受体介导的刺激而非细胞因子介导的刺激降低了干扰素γ的产生。抗病毒疗法迅速降低了肝脏炎症，MAIT细胞活化和细胞毒性，并增加了肝内而非血液T细胞中MAIT细胞的频率。在抗病毒治疗的12周中，MAIT细胞对T细胞受体介导的刺激的反应没有改变。

结论

在分析使用Sofosbuvir和velpatasvir进行抗病毒治疗之前，期间和之后患有慢性HCV感染的患者的配对血液和肝脏样本时，我们发现肝内MAIT细胞被单核细胞衍生的细胞因子激活，并在HCV诱导的肝炎症中耗竭。