I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Sci Rep. 2019 Jul 23;9(1):10624. doi: 10.1038/s41598-019-47024-8.
The combined regulation of a network of inhibitory and activating T cell receptors may be a critical step in the development of chronic HCV infection. Ex vivo HCV MHC class I + II tetramer staining and bead-enrichment was performed with baseline and longitudinal PBMC samples of a cohort of patients with acute, chronic and spontaneously resolved HCV infection to assess the expression pattern of the co-inhibitory molecule TIGIT together with PD-1, BTLA, Tim-3, as well as OX40 and CD226 (DNAM-1) of HCV-specific CD4+ T cells, and in a subset of patients of HCV-specific CD8+ T cells. As the main result, we found a higher expression level of TIGIT+ PD-1+ on HCV-specific CD4+ T cells during acute and chronic HCV infection compared to patients with spontaneously resolved HCV infection (p < 0,0001). Conversely, expression of the complementary co-stimulatory receptor of TIGIT, CD226 (DNAM-1) was significantly decreased on HCV-specific CD4+ T cells during chronic infection. The predominant phenotype of HCV-specific CD4+ T cells during acute and chronic infection was TIGIT+, PD-1+, BTLA+, Tim-3-. This comprehensive phenotypic study confirms TIGIT together with PD-1 as a discriminatory marker of dysfunctional HCV-specific CD4+ T cells.
抑制性和激活性 T 细胞受体网络的联合调控可能是慢性 HCV 感染发展的关键步骤。使用急性、慢性和自发性 HCV 感染患者队列的基线和纵向 PBMC 样本进行 HCV MHC 类 I + II 四聚体染色和珠富集，以评估共抑制分子 TIGIT 与 PD-1、BTLA、Tim-3 以及 OX40 和 CD226（DNAM-1）的表达模式，同时评估 HCV 特异性 CD4+ T 细胞和 HCV 特异性 CD8+ T 细胞亚群的表达模式。主要结果显示，与自发性 HCV 感染患者相比，在急性和慢性 HCV 感染期间，HCV 特异性 CD4+ T 细胞上 TIGIT+PD-1+的表达水平更高（p<0.0001）。相反，在慢性感染期间，HCV 特异性 CD4+ T 细胞上 TIGIT 的互补共刺激受体 CD226（DNAM-1）的表达显著降低。急性和慢性感染期间 HCV 特异性 CD4+ T 细胞的主要表型为 TIGIT+、PD-1+、BTLA+、Tim-3-。这项全面的表型研究证实 TIGIT 与 PD-1 一起作为功能失调的 HCV 特异性 CD4+ T 细胞的鉴别标志物。
