Department of Infectious Diseases II, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Xinxiang, Henan Province, China.
Department of Thyroid Breast and Vascular Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Xinxiang, Henan Province, China.
Biomed Pharmacother. 2017 Oct;94:386-393. doi: 10.1016/j.biopha.2017.07.134. Epub 2017 Aug 1.
Both Galectin 9 (Gal-9)/T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) pathway and follicular helper CD4 T (Tfh) cells play important roles in persistent hepatitis C virus (HCV) infection. Thus, we aimed to investigate the regulatory role of interaction between Gal-9/TIM-3 pathway and Tfh cells in chronic hepatitis C. A total of 44 chronic hepatitis C patients and 19 normal controls (NCs) were enrolled in this study. Purified CD4 T cells were cultured by TIM-3 Fc protein, recombinant Gal-9, or IL-21 for 48h. TIM-3 expression, Tfh proportion, and IL-21 production was measured, respectively. The immunomodulatory role of Gal-9/TIM-3 and IL-21 was also investigated in HCV cell culture system in vitro. We found that the percentage corresponding to both TIM-3-positive and CXCR5ICOS Tfh cells within CD4 T cells, which correlated with HCV RNA replication, was significantly elevated in patients with chronic hepatitis C in comparison with those in NCs. Moreover, blockade of Gal-9/TIM-3 pathway by TIM-3 Fc protein increased Tfh cells proportion, IL-21 mRNA and protein expression within purified CD4 T cells, while activation of Gal-9/TIM-3 signaling by Gal-9 stimulation decreased IL-21 production in both patients with chronic HCV infection and healthy individuals. Meanwhile, high concentrations (100 and 200ng/mL) of IL-21 stimulation also elevated TIM-3 expression on CD4 T cells in chronic hepatitis C. Furthermore, TIM-3 blockage and IL-21 stimulation suppressed mRNA expressions of HCV-induced antiviral proteins (myxovirus resistance A and oligoadenylate synthetase) in Huh7.5 cells without affecting viral replication in HCV cell culture system. The interaction between Gal-9/TIM-3 pathway and Tfh cells contributed to viral persistent in chronic HCV infection, which might be pivotal for development of new therapeutic approaches for chronic hepatitis C.
Galectin 9 (Gal-9)/T 细胞免疫球蛋白和粘蛋白结构域包含蛋白 3 (TIM-3) 通路和滤泡辅助性 CD4 T (Tfh) 细胞在持续性丙型肝炎病毒 (HCV) 感染中发挥重要作用。因此，我们旨在研究 Gal-9/TIM-3 通路与 Tfh 细胞相互作用在慢性丙型肝炎中的调节作用。本研究共纳入 44 例慢性丙型肝炎患者和 19 例正常对照 (NC)。通过 TIM-3Fc 蛋白、重组 Gal-9 或 IL-21 培养纯化的 CD4 T 细胞 48h，分别检测 TIM-3 表达、Tfh 比例和 IL-21 产生。还在体外 HCV 细胞培养系统中研究了 Gal-9/TIM-3 和 IL-21 的免疫调节作用。我们发现，与 NC 相比，慢性丙型肝炎患者 CD4 T 细胞中同时表达 TIM-3 和 CXCR5ICOS 的 Tfh 细胞比例与 HCV RNA 复制相关，显著升高。此外，通过 TIM-3Fc 蛋白阻断 Gal-9/TIM-3 通路增加了纯化的 CD4 T 细胞内 Tfh 细胞比例、IL-21mRNA 和蛋白表达，而 Gal-9 刺激激活 Gal-9/TIM-3 信号降低了慢性 HCV 感染患者和健康个体中 IL-21 的产生。同时，高浓度 (100 和 200ng/mL) 的 IL-21 刺激也增加了慢性丙型肝炎患者 CD4 T 细胞上 TIM-3 的表达。此外，TIM-3 阻断和 IL-21 刺激抑制了 Huh7.5 细胞中 HCV 诱导的抗病毒蛋白 (流感病毒抗性 A 和寡聚腺苷酸合成酶) 的 mRNA 表达，而在 HCV 细胞培养系统中不影响病毒复制。Gal-9/TIM-3 通路与 Tfh 细胞的相互作用导致慢性 HCV 感染中的病毒持续存在，这可能是开发慢性丙型肝炎新治疗方法的关键。
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