Regulation of dendritic cell function and cell-based therapy in chronic hepatitis C virus infection

先天免疫反应和获得性免疫反应的顺序激活对病毒的清除至关重要。树突状细胞(DC)通过Toll样受体(TLR)或维甲酸诱导基因-I(RIG-I)感知病毒感染，导致I型干扰素(IFN)和炎性细胞因子的分泌。血树突状细胞包括髓系树突状细胞(MDC)和浆细胞样树突状细胞(PDC)两个亚群。在慢性丙型肝炎患者中，与健康受试者相比，这两个DC亚群都降低了。此外，在丙型肝炎病毒感染患者中，MDC和PDC在刺激T细胞增殖和细胞因子分泌方面存在功能障碍。在丙型肝炎病毒感染者的MDC中，无论TLR2、TLR4和RIG-I的表达水平高于对照组，TLR/RIG-I介导的干扰素-β、肿瘤坏死因子-α或IL-12p70的诱生水平均低于未感染的供者。这些结果表明，在丙型肝炎病毒感染中，DC中TLR/RIG-I下游的信号转导严重受损。为了搜索…为进一步阐明上述DC功能障碍在丙型肝炎病毒感染中的作用机制，我们将被嵌合的HCVE1/E2蛋白包裹的伪丙型肝炎病毒颗粒接种到健康供者的MDC或PDC中。伪丙型丙型肝炎病毒只进入MDC，而不进入PDC，这表明丙型肝炎病毒的目标是感染髓系亚群。然而，关于丙型肝炎病毒诱导的PDC功能障碍的机制仍未得到解答。关于丙型肝炎病毒感染中适应性免疫系统的普遍损害，如病毒特异性的CD4^+或CD8^+T细胞，已有累积报告发表。自然产生的调节性T细胞(Tregs)是一种特殊的T细胞亚群，能够抑制自身反应性T细胞。为了阐明Treg在慢性丙型肝炎感染中的作用，我们比较了患者和未感染的供者Treg的频率和功能。慢性丙型肝炎患者外周血Tregs的频率和抑制能力高于健康人，ALT持续正常的患者比活动性肝炎患者更多。这些结果表明，丰富的Treg有助于维持低级别的肝脏炎症，可能是通过抑制炎性Th1细胞。总之，树突状细胞协调的先天免疫细胞和获得性免疫细胞之间的积极和相互作用在形成丙型肝炎病毒感染的免疫发病机制中至关重要。较少

Sequential activation of innate and adaptive immune response is crucial for virus elimination. Dendritic cells (DCs) sense virus infection via toll-like receptors (TLR) or retinoic acid inducible gene-I (RIG-I), resulting in the secretion of type-I interferons (IFN) and inflammatory cytokines. Blood DC consist of two subsets; myeloid DC (MDC) and plasmacytoid DC (PDC). In chronic hepatitis C patients, both of these DC subsets decreased compared to healthy subjects. Furthermore, MDC and PDC are functionally impaired in HCV-infected patients in the ability to stimulate T cell proliferation as well as cytokine secretion. In MDC from HCV-infected patients, regardless of higher expression of TLR2, TLR4 and RIG-I compared to the controls, the levels of TLR/RIG-I-mediated IFN-β, TNF-α or IL-12p70 induction are lower than those in uninfected donors. These results suggest that the signal transduction in the downstream of TLR/RIG-I in DC is profoundly impaired in HCV infection. In order to searc … More h for the mechanisms of above-mentioned DC malfunction in HCV infection, we inoculated pseudo-HCV particles, covered by chimeric HCV E1/E2 protein, to MDC or PDC recovered from healthy donors. Pseudo-HCV enters only MDC but not PDC, suggesting that HCV aims to infect myeloid subsets. However, unanswered question still remains for the mechanisms of HCV-induced PDC dysfunction. Cumulative reports have been published for pervasive impairment in adaptive immune system in HCV infection, such as virus-specific CD4^+ or CD8^+ T cells. Naturally occurring regulatory T cells (Tregs) are specialized T cell subsets that are capable of suppressing auto-reactive T cells. In order to clarify the roles of Treg in chronic HCV infection, we compared the frequency and function of Tregs between the patients and uninfected donors. Peripheral Tregs in chronic HCV infection is greater in frequency and in suppressive ability than those in healthy counterparts, much more in patients with persistently normal ALT levels compared to those with active hepatitis. These results imply that the abundance of Treg is beneficial for the maintenance of low-grade liver inflammation, possibly by suppressing inflammatory Th1 cells. In conclusion, active and reciprocal interactions among innate and adaptive immune cells, which are orchestrated by DC, are critical in shaping immuno-pathogenesis of HCV infection. Less