DC-like cell-dependent activation of human natural killer cells by the bisphosphonate zoledronic acid is regulated by γδ T lymphocytes

Bisphosphonates are mainly used for the inhibition of osteoclast-mediated bone resorption but also have been shown to induce gamma delta T-cell activation. Using IL-2-primed cultures of CD56(+) peripheral blood mononuclear cells, we show here that zoledronic acid (zoledronate) could induce IFN-gamma production not only in gamma delta T lymphocytes but, surprisingly, also in natural killer (NK) cells in a manner that depended on antigen-presenting cells, which share properties of inflammatory monocytes and dendritic cells (DCs; here referred to as DC-like cells). In the presence of gamma delta T lymphocytes, DC-like cells were rapidly eliminated, and NK cell IFN-gamma production was silenced. Conversely, in the absence of gamma delta T lymphocytes, DC-like cells were spared, allowing NK cell IFN-gamma production to proceed. gamma delta T cell-independent NK cell activation in response to zoledronate was because of downstream depletion of endogenous prenyl pyrophosphates and subsequent caspase-1 activation in DC-like cells, which then provide mature IL-18 and IL-1 beta for the activation of IL-2-primed NK cells. Pharmacologic inhibition of caspase-1 almost abolished IFN-gamma production in NK cells and gamma delta T lymphocytes, indicating that caspase-1-mediated cytokine maturation is the crucial mechanism underlying innate lymphocyte activation in response to zoledronate. (Blood. 2011;118(10):2743-2751)