Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
J Immunol. 2013 Jul 1;191(1):293-301. doi: 10.4049/jimmunol.1202100. Epub 2013 May 22.
More than 350 million people are chronically infected with hepatitis B virus, and dysfunctional T cell responses contribute to persistent viral infection and immunopathogenesis in chronic hepatitis B (CHB). However, the underlying mechanisms of T cell hyporesponsiveness remain largely undefined. Given the important role of microRNA-146a (miR-146a) in diverse aspects of lymphocyte function, we investigated the potential role and mechanism of miR-146a in regulating T cell immune responses in CHB. We found that miR-146a expression in T cells is significantly upregulated in CHB compared with healthy controls, and miR-146a levels were correlated with serum alanine aminotransaminase levels. Both inflammatory cytokines and viral factors led to miR-146a upregulation in T cells. Stat1 was identified as a miR-146a target that is involved in antiviral cytokine production and the cytotoxicity of CD4(+) and CD8(+) T cells. In vitro blockage of miR-146a in T cells in CHB greatly enhanced virus-specific T cell activity. Therefore, our work demonstrates that miR-146a upregulation in CHB causes impaired T cell function, which may contribute to immune defects and immunopathogenesis during chronic viral infection.
超过 3.5 亿人患有慢性乙型肝炎病毒感染，功能失调的 T 细胞反应导致慢性乙型肝炎（CHB）中的持续病毒感染和免疫发病机制。然而，T 细胞低反应性的潜在机制在很大程度上仍未得到明确。鉴于 microRNA-146a（miR-146a）在淋巴细胞功能的各个方面都具有重要作用，我们研究了 miR-146a 在调节 CHB 中的 T 细胞免疫反应中的潜在作用和机制。我们发现，与健康对照组相比，CHB 患者 T 细胞中的 miR-146a 表达显著上调，并且 miR-146a 水平与血清丙氨酸氨基转移酶水平相关。炎症细胞因子和病毒因子均导致 T 细胞中 miR-146a 的上调。Stat1 被鉴定为 miR-146a 的靶标，参与抗病毒细胞因子的产生和 CD4(+)和 CD8(+)T 细胞的细胞毒性。在 CHB 中，T 细胞中 miR-146a 的体外阻断大大增强了病毒特异性 T 细胞的活性。因此，我们的工作表明，CHB 中 miR-146a 的上调导致 T 细胞功能受损，这可能导致慢性病毒感染期间的免疫缺陷和免疫发病机制。
