Division of Infectious Diseases, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
J Immunol. 2014 Jan 15;192(2):649-57. doi: 10.4049/jimmunol.1302069. Epub 2013 Dec 13.
Coinfection of hepatitis B virus (HBV) with hepatitis C virus (HCV) is quite common, leading to an increase in morbidity and mortality. As such, HBV vaccination is recommended in HCV-infected individuals. However, HBV vaccine responses in HCV-infected individuals are often blunted compared with uninfected populations. The mechanism for this failure of vaccine response in HCV-infected subjects remains unclear. In this study, we investigated the expression and function of an inhibitory receptor, killer cell lectin-like receptor subfamily G member 1 (KLRG1), in the regulation of CD4(+) T cells and HBV vaccine responses during HCV infection. We demonstrated that KLRG1 was overexpressed on CD4(+) T cells from HCV-infected, HBV vaccine nonresponders compared with HBV vaccine responders. The capacity of CD4(+) T cells to proliferate and secrete IL-2 cytokine was inversely associated with the level of KLRG1 expression. Importantly, blocking KLRG1 signaling resulted in a significant improvement in CD4(+) T cell proliferation and IL-2 production in HCV-infected, HBV vaccine nonresponders in response to TCR stimulation. Moreover, blockade of KLRG1 increased the phosphorylation of Akt (Ser(473)) and decreased the expression of cell cycle inhibitors p16(ink4a) and p27(kip1), which subsequently enhanced the expression of cyclin-dependent kinase 2 and cyclin E. These results suggest that the KLRG1 pathway impairs CD4(+) T cell responses to neoantigen and induces a state of immune senescence in individuals with HCV infection, raising the possibility that blocking this negative-signaling pathway might improve HBV vaccine responses in the setting of chronic viral infection.
乙型肝炎病毒 (HBV) 与丙型肝炎病毒 (HCV) 的合并感染较为常见，导致发病率和死亡率增加。因此，建议对 HCV 感染者进行 HBV 疫苗接种。然而，与未感染者相比，HCV 感染者的 HBV 疫苗反应通常较为迟钝。导致 HCV 感染者疫苗反应失败的机制尚不清楚。在这项研究中，我们研究了抑制性受体杀伤细胞凝集素样受体亚家族 G 成员 1（KLRG1）在 HCV 感染期间调节 CD4+T 细胞和 HBV 疫苗反应中的表达和功能。我们证明，与 HBV 疫苗应答者相比，HCV 感染、HBV 疫苗无应答者的 CD4+T 细胞上过度表达了 KLRG1。CD4+T 细胞增殖和分泌白细胞介素 2（IL-2）细胞因子的能力与 KLRG1 表达水平呈负相关。重要的是，阻断 KLRG1 信号可显著改善 HCV 感染、HBV 疫苗无应答者的 CD4+T 细胞增殖和对 TCR 刺激的 IL-2 产生。此外，阻断 KLRG1 增加了 Akt（Ser（473））的磷酸化，并降低了细胞周期抑制剂 p16(ink4a)和 p27(kip1)的表达，随后增强了细胞周期蛋白依赖性激酶 2 和细胞周期蛋白 E 的表达。这些结果表明，KLRG1 途径会损害 CD4+T 细胞对新抗原的反应，并在 HCV 感染者中诱导免疫衰老状态，这提示阻断这种负信号通路可能改善慢性病毒感染患者的 HBV 疫苗反应。
