Barathan Muttiah, Mohamed Rosmawati, Vadivelu Jamuna, Chang Li Yen, Vignesh Ramachandran, Krishnan Jayalakshmi, Sigamani Panneer, Saeidi Alireza, Ram M Ravishankar, Velu Vijayakumar, Larsson Marie, Shankar Esaki M
Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
Department of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
Cell Immunol. 2017 Mar;313:1-9. doi: 10.1016/j.cellimm.2016.12.002. Epub 2016 Dec 16.
Hepatitis C virus (HCV)-specific CD4+ and CD8+ T cells are key to successful viral clearance in HCV disease. Accumulation of exhausted HCV-specific T cells during chronic infection results in considerable loss of protective functional immune responses. The role of T-cell exhaustion in chronic HCV disease remains poorly understood. Here, we studied the frequency of HCV peptide-stimulated T cells expressing negative immune checkpoints (PD-1, CTLA-4, TRAIL, TIM-3 and BTLA) by flow cytometry, and measured the levels of Th1/Th2/Th17 cytokines secreted by T cells by a commercial Multi-Analyte ELISArray™ following in vitro stimulation of T cells using HCV peptides and phytohemagglutinin (PHA). HCV peptide-stimulated CD4+ and CD8+ T cells of chronic HCV (CHC) patients showed significant increase of CTLA-4. Furthermore, HCV peptide-stimulated CD4+ T cells of CHC patients also displayed relatively higher levels of PD-1 and TRAIL, whereas TIM-3 was up-regulated on HCV peptide-stimulated CD8+ T cells. Whereas the levels of IL-10 and TGF-β1 were significantly increased, the levels of pro-inflammatory cytokines IL-2, TNF-α, IL-17A and IL-6 were markedly decreased in the T cell cultures of CHC patients. Chronic HCV infection results in functional exhaustion of CD4+ and CD8+ T cells likely contributing to viral persistence.
丙型肝炎病毒（HCV）特异性CD4+和CD8+ T细胞是HCV疾病中病毒成功清除的关键。慢性感染期间耗竭的HCV特异性T细胞的积累导致保护性功能性免疫反应的大量丧失。T细胞耗竭在慢性HCV疾病中的作用仍知之甚少。在这里，我们通过流式细胞术研究了表达阴性免疫检查点（PD-1、CTLA-4、TRAIL、TIM-3和BTLA）的HCV肽刺激的T细胞的频率，并在使用HCV肽和植物血凝素（PHA）对T细胞进行体外刺激后，通过商业多分析物ELISA芯片™测量T细胞分泌的Th1/Th2/Th17细胞因子的水平。慢性HCV（CHC）患者的HCV肽刺激的CD4+和CD8+ T细胞显示CTLA-4显著增加。此外，CHC患者的HCV肽刺激的CD-4 T细胞也显示出相对较高水平的PD-1和TRAIL，而TIM-3在HCV肽刺激的CD8+ T细胞上上调。虽然CHC患者的T细胞培养物中IL-10和TGF-β1水平显著增加，但促炎细胞因子IL-2、TNF-α、IL-17A和IL-6水平明显降低。慢性HCV感染导致CD4+和CD8+ T细胞功能耗竭，这可能导致病毒持续存在。
