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.

Automated summary

TLR8 expression was up-regulated in NK cells of patients with CHB, but accompanied by insufficient IFN-gamma production. The response of NK cells to TLR8 agonist stimulation was inhibitory in CHB patients. Targeting TLR8 partially rescued the IFN-gamma insufficiency in NK cells, and combining TLR8 agonist with NA therapy could enhance the antiviral effect of NK cells.