慢性乙型肝炎病毒感染者中乙型肝炎病毒特异性 CD8 T 细胞具有记忆样表型，与病毒免疫逃逸有关。
Hepatitis D Virus-Specific CD8 T Cells Have a Memory-Like Phenotype Associated With Viral Immune Escape in Patients With Chronic Hepatitis D Virus Infection.
机构信息
Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland.
Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland.
出版信息
Gastroenterology. 2019 May;156(6):1805-1819.e9. doi: 10.1053/j.gastro.2019.01.035. Epub 2019 Jan 18.
BACKGROUND & AIM: Hepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapid progression to liver cirrhosis. Little is known about HDV-specific T cells and how they contribute to the antiviral immune response and liver disease pathogenesis.
METHODS
We isolated peripheral blood mononuclear cells from 28 patients with chronic HDV and HBV infection, identified HDV-specific CD8 T-cell epitopes, and characterized HDV-specific CD8 T cells. We associated these with HDV sequence variations and clinical features of patients.
RESULTS
We identified 6 CD8 T-cell epitopes; several were restricted by multiple HLA class I alleles. HDV-specific CD8 T cells were as frequent as HBV-specific CD8 T cells but were less frequent than T cells with specificity for cytomegalovirus, Epstein-Barr virus, or influenza virus. The ex vivo frequency of activated HDV-specific CD8 T cells correlated with transaminase activity. CD8 T-cell production of interferon gamma after stimulation with HDV peptides correlated inversely with HDV titer. HDV-specific CD8 T cells did not express the terminal differentiation marker CD57, and fewer HDV-specific than Epstein-Barr virus-specific CD8 T cells were 2B4CD160PD1, a characteristic of exhausted cells. Approximately half of the HDV-specific CD8 T cells had a memory-like PD1CD127TCF1T-bet phenotype, which associated with HDV sequence variants with reduced HLA binding and reduced T-cell activation.
CONCLUSIONS
CD8 T cells isolated from patients with chronic HDV and HBV infection recognize HDV epitopes presented by multiple HLA molecules. The subset of activated HDV-specific CD8 T cells targets conserved epitopes and likely contributes to disease progression. The subset of memory-like HDV-specific CD8 T cells is functional but unable to clear HDV because of the presence of escape variants. ClinicalTrials.gov, Numbers: NCT02511431, NCT00023322, NCT01495585, and NCT00001971. GenBank accession, Number: MK333199-333226.
背景与目的
乙型肝炎病毒（HBV）慢性感染者发生丁型肝炎病毒（HDV）重叠感染会迅速进展为肝硬化。人们对 HDV 特异性 T 细胞知之甚少，也不了解其在抗病毒免疫反应和肝脏疾病发病机制中的作用。
方法
我们从 28 例慢性 HDV 和 HBV 感染患者中分离外周血单个核细胞，鉴定 HDV 特异性 CD8 T 细胞表位，并对 HDV 特异性 CD8 T 细胞进行特征分析。我们将这些与 HDV 序列变异和患者的临床特征联系起来。
结果
我们鉴定了 6 个 CD8 T 细胞表位；其中一些受多种 HLA Ⅰ类等位基因限制。HDV 特异性 CD8 T 细胞与 HBV 特异性 CD8 T 细胞一样常见，但不如巨细胞病毒、EB 病毒或流感病毒特异性 T 细胞常见。体外激活的 HDV 特异性 CD8 T 细胞的频率与转氨酶活性相关。用 HDV 肽刺激后 CD8 T 细胞产生干扰素γ与 HDV 滴度呈负相关。HDV 特异性 CD8 T 细胞不表达终末分化标志物 CD57，与 EBV 特异性 CD8 T 细胞相比，更少的 HDV 特异性 CD8 T 细胞表达 2B4CD160PD1，这是耗竭细胞的特征。大约一半的 HDV 特异性 CD8 T 细胞具有记忆样 PD1CD127TCF1T-bet 表型，与 HLA 结合降低和 T 细胞激活减少的 HDV 序列变异相关。
结论
从慢性 HDV 和 HBV 感染患者中分离的 CD8 T 细胞识别由多种 HLA 分子呈递的 HDV 表位。活化的 HDV 特异性 CD8 T 细胞亚群针对保守表位，可能有助于疾病进展。记忆样 HDV 特异性 CD8 T 细胞亚群具有功能，但由于存在逃逸变异，无法清除 HDV。ClinicalTrials.gov 注册号：NCT02511431、NCT00023322、NCT01495585 和 NCT00001971。GenBank 注册号：MK333199-333226。
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