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

先天性和适应性免疫应答的顺序激活对于病毒消除至关重要。树突状细胞（Dendritic cells，DC）通过Toll样受体（toll like receptor，TLR）或视黄酸诱导基因I（retinoic acid inducible gene-I，RIG-I）感知病毒感染，分泌I型干扰素（type-I interferon，IFN）和炎性细胞因子。血液DC由两个亚群组成;髓样DC（MDC）和浆细胞样DC（PDC）。在慢性丙型肝炎患者中，与健康受试者相比，这两种DC亚群均减少。此外，在HCV感染患者中，MDC和PDC在刺激T细胞增殖以及细胞因子分泌的能力方面功能受损。在来自HCV感染患者的MDC中，与对照相比，尽管TLR 2、TLR 4和RIG-I的表达更高，但TLR/RIG-I介导的IFN-β、TNF-α或IL-12 p70诱导的水平低于未感染供体的水平。这些结果表明，TLR/RIG-I下游的DC中的信号转导在HCV感染中被深刻地损害。为了搜索 ...更多信息 为了研究HCV感染时DC功能障碍的机制，我们将HCV E1/E2嵌合蛋白覆盖的假HCV颗粒接种到从健康供体回收的MDC或PDC中。伪HCV仅进入MDC而不进入PDC，表明HCV旨在感染髓系亚群。然而，HCV诱导PDC功能障碍的机制仍然是一个悬而未决的问题。HCV感染后获得性免疫系统普遍受损，如病毒特异性CD 4 ^+或CD 8 ^+ T细胞受损，已有累积报道。天然存在的调节性T细胞（TCRs）是能够抑制自身反应性T细胞的特化T细胞亚群。为了阐明Treg在慢性HCV感染中的作用，我们比较了患者和未感染供体之间Treg的频率和功能。慢性HCV感染者的外周血THBVDNA的频率和抑制能力均高于健康对照者，ALT水平持续正常的患者比活动性肝炎患者的THBVDNA的抑制能力更强。这些结果意味着Treg的丰富可能通过抑制炎性Th 1细胞而有利于维持低度肝脏炎症。总之，先天性和适应性免疫细胞之间的积极和互惠的相互作用，这是精心策划的DC，在塑造HCV感染的免疫发病机制是至关重要的。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