IL-18 Responsiveness Defines Limitations in Immune Help for Specialized FcRγ- NK Cells

Despite being prolific innate killers, NK cells are also key helper cells in antiviral defense, influencing adaptive immune responses via interactions with dendritic cells (DCs). In addition to causing NK cell dysfunction, HIV-1 infection contributes to the expansion of a rare population of NK cells deficient in FcR gamma (FcR gamma(-)), an intracellular adaptor protein that associates with CD16. The implications of this inflated NK cell subset in treated HIV-1 infection remain unclear. In this study, we explored the helper function of human NK cells in chronic HIV-1 infection, with a particular focus on characterizing FcR gamma(-) NK cells. Exposure of NK cells to innate DC-derived costimulatory factors triggered their helper activity, defined by their ability to produce IFN-gamma and to drive the maturation of high IL-12-producing DCs. In this setting, however, FcR gamma(-) NK cells were defective at producing the dominant DC-polarizing agent IFN-gamma. The reduced responsiveness of FcR gamma(-) NK cells to IL-18 in particular, which was attributable to impaired inducible expression of IL-18R alpha, extended beyond an inability to produce IFN-gamma, as FcR gamma(-) NK cells showed limited potential to differentiate into CD16(-)/CD25(+)/CD83(+) helper cells. Notwithstanding their deficiencies in responsiveness to innate environmental cues, FcR gamma(-) NK cells responded robustly to adaptive Ab-mediated signaling through CD16. The presence of an expanded population of FcR gamma(-) NK cells with a diminished capacity to respond to IL-18 and to effectively modulate DC function may contribute to disturbances in proper immune homeostasis associated with HIV-1 infection and to defects in the initiation of optimal adaptive antiviral responses.