Innate immunity in hepatitis C virus infection: Interplay among dendritic cells, natural killer cells and natural killer T cells

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‐β or TNF‐α 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‐α, 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‐α 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‐β1. 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‐γ 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.

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