Abstract
Abstract Natural killer (NK) cells are uniquely positioned to positively impact antiviral immunity to HIV-1 due to the pleiotropic nature of their effector functions, including the ability to respond directly to infected cells and to translate environmental cues into functional ‘help’ for other immune cells. In particular, their interplay with dendritic cells (DCs) is powerful in shaping the quality and character of the adaptive immune response. In this study, we explored the ‘helper’ function of NK cells in response to both innate and adaptive stimuli in chronic HIV-1 infection. Freshly isolated NK cells from virally suppressed HIV-1 seropositive individuals were co-cultured for 48h with autologous monocyte-derived immature DCs in the presence or absence of innate stimuli or opsonized target cells. Responding NK cells were assessed for their ability to produce DC-modulating cytokines; DCs harvested from the co-cultures were analyzed for their expression of maturation-associated surface markers, as well as their subsequent ability to produce IL-12p70 and to drive type 1 immunity. DC-derived co-stimulatory factors efficiently activated the ‘helper’ function of NK cells as evidenced by their robust production of IFNγ. Opsonizing antibodies also synergized with IFNα to promote NK ‘helper’ cell activity. Furthermore, interactions between NK cells and DCs induced the development of mature DCs with a heightened ability to produce IL-12p70 and to drive the development of Th1 and cytotoxic T cell responses. Our data demonstrate the capacity of NK cells to enhance DC-mediated immune responses to HIV-1 and, thus, highlight the potential for harnessing the reciprocal crosstalk between NK cells and DCs in the design of novel anti-HIV-1 therapies.
Published Version
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