Innate immunity in hepatitis C virus infection: Interplay among dendritic cells, natural killer cells and natural killer T cells
Innate immunity in hepatitis C virus infection: Interplay among dendritic cells, natural killer cells and natural killer T cells
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DOI：
10.1111/j.1872-034x.2007.00236.x
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发表时间：
2007-10-01
影响因子：
4.2
通讯作者：
Hayashi, Norio
中科院分区：
文献类型：
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作者：
Kanto, Tatsuya;Hayashi, Norio
先天和适应性免疫反应的顺序激活对病毒消除至关重要。因此，我们试图阐明先天免疫系统在丙型肝炎病毒（HCV）感染发病机制中的作用。树突状细胞（DC）通过toll样受体（TLR）或视黄酸诱导基因i （RIG-I）感知病毒感染，导致i型干扰素（IFN）和炎症细胞因子的分泌。血液DC包括两个亚群；髓样DC （MDC）和浆细胞样DC （PDC）。在hcv感染患者的MDC中，尽管TLR2、TLR4和RIG-I的表达高于对照组，但TLR/RIG-I介导的ifn - β或tnf - α诱导水平低于未感染供者。这些结果表明，在HCV感染中，MDC中TLR/ rig - 1下游的信号转导严重受损。在ifn - α的作用下，DC能够表达MHC i类相关链A/B (MICA/B)，并在连接NKG2D后激活自然杀伤细胞（NK）。有趣的是，来自hcv感染患者的DC对外源性ifn - α增强MICA/B表达无反应，不能激活NK细胞。另外，hcv感染患者的NK细胞在表达人白细胞抗原e的肝细胞存在时，通过分泌白细胞介素(IL)-10和转化生长因子- β 1下调DC功能。HCV感染中NK细胞的这种功能改变归因于抑制受体NKG2A/CD94的表达比健康受体增强。被cd1阳性DC激活的不变NKT细胞分泌辅助性t (Th)1和Th2细胞因子，作为免疫调节剂。慢性HCV感染中NKT细胞的频率与健康供者无差异。激活的NKT细胞产生更高水平的IL-13，但ifn - γ水平与健康受试者相当，表明NKT细胞在慢性HCV感染中偏向于th2型。综上所述，DC细胞、NK细胞和NKT细胞之间的交叉对话在形成随后针对HCV的适应性免疫应答中至关重要。
Sequential activation of innate and adaptive immune response is crucial for virus elimination. We thus sought to clarify the role of innate immune system in the pathogenesis of hepatitis C virus (HCV) infection. Dendritic cells (DC) 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 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-beta or TNF-alpha induction are lower than those in uninfected donors. These results suggest that the signal transduction in the downstream of TLR/RIG-I in MDC is profoundly impaired in HCV infection. In response to IFN-alpha, DC are able to express MHC class-I related chain A/B (MICA/B) and activate natural killer (NK) cells following ligation of NKG2D. Interestingly, DC from HCV-infected patients are unresponsive to exogenous IFN-alpha to enhance MICA/B expression and fail to activate NK cells. Alternatively, NK cells from HCV-infected patients downregulate DC functions in the presence of human leukocyte antigen E-expressing hepatocytes by secreting interleukin (IL)-10 and transforming growth factor-beta 1. Such functional alteration of NK cells in HCV infection is ascribed to the enhanced expression of inhibitory receptor NKG2A/CD94 compared to the healthy counterparts. Invariant NKT cells activated by CD1d-positive DC secrete both T-helper (Th)1 and Th2 cytokines, serving as immune regulators. The frequency of NKT cells in chronic HCV infection does not differ from those in healthy donors. Activated NKT cells produce higher levels of IL-13 but comparable levels of IFN-gamma with those from healthy subjects, showing that NKT cells are biased to Th2-type in chronic HCV infection. In conclusion, cross-talks among DC, NK cells and NKT cells are critical in shaping subsequent adaptive immune response against HCV.