肝脏环境和 HCV 复制影响人类 T 细胞表型和抑制性受体的表达。
Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors.
机构信息
Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
出版信息
Gastroenterology. 2014 Feb;146(2):550-61. doi: 10.1053/j.gastro.2013.10.022. Epub 2013 Oct 19.
BACKGROUND & AIMS: There is an unclear relationship between inhibitory receptor expression on T cells and their ability to control viral infections. Studies of human immune cells have been mostly limited to T cells from blood, which is often not the site of infection. We investigated the relationship between T-cell location, expression of inhibitory receptors, maturation, and viral control using blood and liver T cells from patients with hepatitis C virus (HCV) and other viral infections.
METHODS
We analyzed 36 liver samples from HCV antibody-positive patients (30 from patients with chronic HCV infection, 5 from patients with sustained virological responses to treatment, and 1 from a patient with spontaneous clearance) with 19 paired blood samples and 51 liver samples from HCV-negative patients with 17 paired blood samples. Intrahepatic and circulating lymphocytes were extracted; T-cell markers and inhibitory receptors were quantified for total and virus-specific T cells by flow cytometry.
RESULTS
Levels of the markers PD-1 and 2B4 (but not CD160, TIM-3, or LAG-3) were increased on intrahepatic T cells from healthy and diseased liver tissues compared with T cells from blood. HCV-specific intrahepatic CD8(+) T cells from patients with chronic HCV infection were distinct in that they expressed TIM-3 along with PD-1 and 2B4. In comparison, HCV-specific CD8(+) T cells from patients with sustained virological responses and T cells that recognized cytomegalovirus lacked TIM-3 but expressed higher levels of LAG-3; these cells also had different memory phenotypes and proliferative capacity.
CONCLUSIONS
T cells from liver express different inhibitory receptors than T cells from blood, independent of liver disease. HCV-specific and cytomegalovirus-specific CD8(+) T cells can be differentiated based on their expression of inhibitory receptors; these correlate with their memory phenotype and levels of proliferation and viral control.
背景与目的
T 细胞抑制性受体的表达与其控制病毒感染的能力之间的关系尚不清楚。对人类免疫细胞的研究大多局限于血液中的 T 细胞，而血液通常不是感染部位。我们通过研究丙型肝炎病毒（HCV）和其他病毒感染患者的血液和肝脏 T 细胞，调查了 T 细胞位置、抑制性受体表达、成熟度与病毒控制之间的关系。
方法
我们分析了 36 份来自 HCV 抗体阳性患者（慢性 HCV 感染患者 30 例，治疗后持续病毒学应答患者 5 例，自发清除患者 1 例）的肝脏样本，其中 19 份配对的血液样本，以及 51 份 HCV 阴性患者的肝脏样本，其中 17 份配对的血液样本。提取肝内和循环淋巴细胞；通过流式细胞术对总 T 细胞和病毒特异性 T 细胞定量检测 T 细胞标志物和抑制性受体。
结果
与血液 T 细胞相比，来自健康和疾病肝组织的 T 细胞中 PD-1 和 2B4（但不是 CD160、TIM-3 或 LAG-3）标志物水平升高。慢性 HCV 感染患者的 HCV 特异性肝内 CD8(+)T 细胞明显表达 TIM-3，同时表达 PD-1 和 2B4。相比之下，具有持续病毒学应答的 HCV 特异性 CD8(+)T 细胞和识别巨细胞病毒的 T 细胞缺乏 TIM-3，但表达更高水平的 LAG-3；这些细胞还具有不同的记忆表型和增殖能力。
结论
与血液 T 细胞相比，来自肝脏的 T 细胞表达不同的抑制性受体，而与肝脏疾病无关。基于抑制性受体的表达，可以区分 HCV 特异性和巨细胞病毒特异性 CD8(+)T 细胞；这些与它们的记忆表型、增殖水平和病毒控制相关。
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