Yonkers Nicole L, Rodriguez Benigno, Milkovich Kimberly A, Asaad Robert, Lederman Michael M, Heeger Peter S, Anthony Donald D
Department of Medicine, Divisions of Infectious and Rheumatic Diseases, Veterans Affairs Medical Center, University Hospitals of Cleveland and Cleveland Clinic Foundation, Cleveland, OH 44106, USA.
J Immunol. 2007 Apr 1;178(7):4436-44. doi: 10.4049/jimmunol.178.7.4436.
Chronic hepatitis C virus (HCV) infection is characterized by diminished numbers and function of HCV-reactive T cells and impaired responses to immunization. Because host response to viral infection likely involves TLR signaling, we examined whether chronic HCV infection impairs APC response to TLR ligand and contributes to the origin of dysfunctional T cells. Freshly purified myeloid dendritic cells (MDC) and plasmacytoid DC (PDC) obtained from subjects with chronic HCV infection and healthy controls were exposed to TLR ligands (poly(I:C), R-848, or CpG), in the presence or absence of cytokine (TNF-alpha or IL-3), and examined for indices of maturation and for their ability to activate allogeneic naive CD4 T cells to proliferate and secrete IFN-gamma. TLR ligand was observed to enhance both MDC and PDC activation of naive CD4 T cells. Although there was increased CD83 and CD86 expression on MDC from HCV-infected persons, the ability of MDC to activate naive CD4 T cells in the presence or absence of poly(I:C) or TNF-alpha did not differ between HCV-infected and healthy control subjects. In contrast, PDC from HCV-infected persons had reduced activation marker (HLA-DR) and cytokine (IFN-alpha) expression upon R-848 stimulation, and these were associated with impaired activation of naive CD4 T cells. These data indicate that an impaired PDC responsiveness to TLR ligation may play an important role in the fundamental and unexplained failure to induce new T cell responses to HCV Ags and to other new Ags as a consequence of HCV infection.
慢性丙型肝炎病毒（HCV）感染的特征是HCV反应性T细胞数量减少和功能受损，以及免疫反应受损。由于宿主对病毒感染的反应可能涉及Toll样受体（TLR）信号传导，我们研究了慢性HCV感染是否会损害抗原呈递细胞（APC）对TLR配体的反应，并导致功能失调的T细胞的产生。从慢性HCV感染患者和健康对照者中新鲜纯化的髓样树突状细胞（MDC）和浆细胞样树突状细胞（pDC），在有或没有细胞因子（肿瘤坏死因子-α或白细胞介素-3）存在的情况下，暴露于TLR配体（聚肌胞苷酸、R-848或CpG），并检测其成熟指标以及激活同种异体初始CD4 T细胞增殖和分泌γ干扰素的能力。观察到TLR配体增强了MDC和pDC对初始CD4 T细胞 的激活作用。虽然来自HCV感染者的MDC上CD83和CD86表达增加，但在有或没有聚肌胞苷酸或肿瘤坏死因子-α存在的情况下，HCV感染者和健康对照者的MDC激活初始CD4 T细胞的能力没有差异。相反，来自HCV感染者的pDC在R-848刺激后激活标志物（HLA-DR）和细胞因子（α干扰素）表达降低，这些与初始CD4 T细胞激活受损有关。这些数据表明，pDC对TLR连接反应受损可能在HCV感染导致的无法诱导针对HCV抗原及其他新抗原产生新的T细胞反应这一根本且无法解释的现象中起重要作用。
