Ye B, Liu X, Li X, Kong H, Tian L, Chen Y
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Cell Death Dis. 2015 Mar 19;6(3):e1694. doi: 10.1038/cddis.2015.42.
Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells. In humans, chronic HBV infection often shows weak or absent virus-specific T-cell reactivity, which is described as the 'exhaustion' state characterized by poor effector cytotoxic activity, impaired cytokine production and sustained expression of multiple inhibitory receptors, such as programmed cell death-1 (PD-1), lymphocyte activation gene-3, cytotoxic T lymphocyte-associated antigen-4 and CD244. As both CD4(+) and CD8(+) T cells participate in the immune responses against chronic hepatitis virus through distinct manners, compelling evidences have been proposed, which restore the anti-viral function of these exhausted T cells by blocking those inhibitory receptors with its ligand and will pave the way for the development of more effective immunotherapeutic and prophylactic strategies for the treatment of chronic infectious diseases. A large number of studies have stated the essentiality of T-cell exhaustion in virus-infected diseases, such as LCMV, hepatitis C virus (HCV), human immunodeficiency virus infections and cancers. Besides, the functional restoration of HCV- and HIV-specific CD8(+) T cells by PD-1 blockade has already been repeatedly verified, and also for the immunological control of tumors in humans, blocking the PD-1 pathway could be a major immunotherapeutic strategy. Although the specific molecular pathways of T-cell exhaustion remain ambiguous, several transcriptional pathways have been implicated in T-cell exhaustion recently; among them Blimp-1, T-bet and NFAT2 were able to regulate exhausted T cells during chronic viral infection, suggesting a distinct lineage fate for this sub-population of T cells. This paper summarizes the current literature relevant to T-cell exhaustion in patients with HBV-related chronic hepatitis, the options for identifying new potential therapeutic targets to treat HBV infection and highlights priorities for further study.
乙型肝炎病毒（HBV）感染是炎症性肝病的主要病因，其临床康复及有效的抗病毒治疗与效应T细胞对病毒的持续控制有关。在人类中，慢性HBV感染常常表现出较弱的或缺失的病毒特异性T细胞反应性，这被描述为“耗竭”状态，其特征为效应细胞毒性活性差、细胞因子产生受损以及多种抑制性受体的持续表达，如程序性细胞死亡蛋白1（PD-1）、淋巴细胞激活基因3、细胞毒性T淋巴细胞相关抗原4和CD244。由于CD4(+)和CD8(+) T细胞均通过不同方式参与针对慢性肝炎病毒的免疫反应，因此已有确凿证据表明，通过用其配体阻断这些抑制性受体来恢复这些耗竭T细胞的抗病毒功能，将为开发更有效的慢性传染病免疫治疗和预防策略铺平道路。大量研究表明T细胞耗竭在病毒感染性疾病如淋巴细胞脉络丛脑膜炎病毒（LCMV）、丙型肝炎病毒（HCV）、人类免疫缺陷病毒感染及癌症中至关重要。此外，通过阻断PD-1已反复证实HCV特异性和HIV特异性CD8(+) T细胞的功能得以恢复，而且对于人类肿瘤的免疫控制而言，阻断PD-1通路可能是一种主要的免疫治疗策略。尽管T细胞耗竭的具体分子途径仍不明确，但最近有几种转录途径与T细胞耗竭有关；其中B淋巴细胞诱导成熟蛋白1（Blimp-1）、T盒转录因子（T-bet）和活化T细胞核因子2（NFAT2）能够在慢性病毒感染期间调节耗竭的T细胞，这表明该亚群T细胞具有独特的谱系命运。本文总结了目前与HBV相关慢性肝炎患者T细胞耗竭相关的文献、识别治疗HBV感染新潜在治疗靶点的选择，并强调了进一步研究的重点。
