[15] Antiviral therapy or blockage of interleukin (IL)-10+/− TGF-β resulted in a partially enhanced activation state of NK cells and restored the capacity of NK cells to produce IFN-γ in vivo.[14, 16] HBV persistence also upregulates the expression of co-suppressive molecules (such as T-cell immunoglobulin and mucin domain 3 (Tim-3), programmed death 1 [PD-1]) on surface of NK cells and downregulates the expression of NKG2D ligands, MHC class I-related chain A (MICA), on hepatocytes,

both contribute to inhibition of NK cell cytolysis ability and IFN-γ production, leading to NK cell dysfunction.[17, 18] GSK-3 phosphorylation NKT cells are greatly enriched in the liver and can rapidly detect and respond to Sorafenib mouse hepatocytes infected by HBV.[19] α-GalCer-activated invariant NK T (iNKT) cells are able to inhibit HBV replication

in vivo,[20] suggesting that NKT cells are part of an early sensing system and may further prime HBV-specific adaptive immune response. However, the number of circulating iNKT cells in CHB patients is lower compared with healthy donors and inactive healthy HBV carriers, while it increases to normal levels when HBV infection was controlled by antiviral therapy with telbivudine.[21, 22] In addition, as the messenger between the innate and adaptive immune system, plasmocytoid dendritic cells (pDCs) display diminished capacity to produce IFN-α in chronic HBV patients.[23-25] Moreover, the interaction between NK cells and pDCs were suppressed by HBV selleck inhibitor infection, as defined by inhibition of pDC-induced IFN-γ production by NK cells.[26] Untergasser A confirmed that circulating DCs take up HBV antigens and thus impairing the number and function of these cells.[27] The dysfunctional pDCs may further promote the immunopathogenesis of HBV infection. Collectively, the

persistence of HBV not only directly inhibits PRR recognition and the antiviral signaling pathways, leading to cell-intrinsic immunotolerance, but also suppresses the frequency and function of systemic innate immune cells (including NK, NKT, and pDCs), resulting in systemic innate immune tolerance (Fig. 1). HBV persistence severely impairs the function of CD8+ T cells, especially HBV-specific T cells. In CHB-infected patients, CD8+ T cells lose their ability to proliferate and antiviral function that is characterized by excessive inhibitory signals, low cytokine production, and T cell exhaustion.[28] As a co-inhibitory receptor, programmed death 1 (PD-1) is known to be involved in the immune response to infection, particularly chronic viral infection, and attenuate T cell activation by transducing co-inhibitory signaling.