TLR8 agonist partially improves IFN-γ deficiency of NK cells in chronic hepatitis B through the synergy of monocytes

Background: Natural killer (NK) cells exhibit a selective deficiency of IFN-gamma production in chronic hepatitis B (CHB). Toll-like receptor 8 (TLR8) agonists could induce IFN-gamma production in immune cells, although their effects on the deficiency in NK cells remain unclear. Aims: To investigate TLR8 expression in NK cells and the effect of TLR8 agonists in patients with CHB Methods: We enrolled 32 patients with CHB and 19 healthy controls to assess TLR8 expression and IFN-gamma production in NK cells. The sorted NK cells and monocytes were co-cultured to compare the extent of IFN-gamma and IL-10 production after TLR8 agonist ssRNA40 stimulation. The synergic effect of NK cells and monocytes was assessed by blocking IL-12 and IL-18. We recruited another 22 patients with CHB undergoing nucleotide analogue (NA) therapy to explore the impact of antiviral treatment on the ssRNA40-mediated response of NK cells. Results: In patients with CHB, TLR8 expression in NK cells was up-regulated, accompanied by insufficient IFN-gamma production. The enhanced IFN-gamma secretion by ssRNA40 in NK cells depended on monocyte-derived IL-12 and IL-18. NK cells displayed an imbalanced response to ssRNA40 in patients with CHB with a weak increase in IFN-gamma despite a higher IL-10 production. The response was improved in patients with CHB undergoing NA therapy. Conclusions: In patients with CHB, targeting TLR8 partially rescues the IFN-gamma insufficiency in NK cells. However, NK cells show an inhibitory response to TLR8 agonist stimulation. TLR8 agonist combined with NA may enhance the antiviral effect of NK cells.