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

Abstract

Bisphosphonates are mainly used for the inhibition of osteoclast-mediated bone resorption but also have been shown to induce ␥␦ T-cell activation. Using IL-2-primed cultures of CD56 ؉ peripheral blood mononuclear cells, we show here that zoledronic acid (zoledronate) could induce IFN-␥ production not only in ␥␦ 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 ␥␦ T lymphocytes, DC-like cells were rapidly eliminated, and NK cell IFN-␥ production was silenced. Conversely, in the absence of ␥␦ T lymphocytes, DClike cells were spared, allowing NK cell IFN-␥ production to proceed. ␥␦ T cellindependent 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␤ for the activation of IL-2-primed NK cells. Pharmacologic inhibition of caspase-1 almost abolished IFN-␥ production in NK cells and ␥␦ 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) IntroductionThe bisphosphonates zoledronate and pamidronate are approved by the Food and Drug Administration for the treatment of metastatic bone disease of hematopoietic tumors such as multiple myeloma 1,2 and nonhematopoietic tumors such as breast 3 and prostate cancer. 4 Inhibition of farnesyl pyrophosphate synthase, an enzyme of the mevalonate pathway for cholesterol biosynthesis and protein prenylation, 5 is one important mechanism for bisphosphonate effects on bone resorption. 1,4 Inhibition of farnesyl pyrophosphate synthase leads to farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) deprivation and the subsequent failure to perform farnesylation and geranylgeranylation of small guanosine triphosphatases (GTPases) of the RAS superfamily. Inhibition of RAS signaling because of the disruption of membrane anchoring of these GTPases eventually prevents osteoclast-mediated bone resorption. 6,7 In addition to their effects on bone metabolism, bisphosphonates may have immunomodulatory effects, particularly on the innate immune system. [8][9][10][11] Evidence for the stimulation of ␥␦ T lymphocytes by bisphosphonates was obtained when expansion of ␥␦ T lymphocytes was observed in patients who had acute-phase reactions after their first treatment with pamidronate. 12 Inhibition of FPP synthase by bisphosphonates leads to the accumulation of isopentenyl pyrophosphate that can be specifically recognized by ␥␦ T lymphocytes expressing the V␦2V␥9 T-cell receptors. 13 Hematopoietic tumor cell lines such as Daudi (Burkitt lymphoma) or RPMI 8226 (myeloma) are specifically recognized and lysed by these ␥␦ T lymphocytes in vitro. 14,15 Moreover, ␥␦ T lymphocytes have recently been...

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

“…1B demonstrate that reconstitution with GGPP abolished IL-18 release, and inhibition of caspase-1 with the specific inhibitor YVAD (37) also abrogated IL-18 secretion (Fig. 1B), which was in accordance with our previous findings (29). IL-18 is known principally for its ability to induce IFN-g production, and cytokines, such as IL-2, can cooperate with IL-18 to enhance IFN-g production in a synergistic fashion (38).…”

“…1). We showed previously that GGPP deprivation can result in functional maturation and release of IL-1b and IL-18 after proteolytic cleavage of the inactive proforms by caspase-1 and that endogenous IL-18 is the main mediator during zoledronate-induced gd T cell activation (3,28,29).…”

“…IL-18, which is a stress-related, caspase-1-processed cytokine (31), was implicated in zoledronateinduced NK cell and gd T cell activation (29) and was shown to costimulate zoledronate-induced, IL-2-driven gd T cell expansion (32). A population of CD56 bright CD11c + NK cells was postulated to mediate the stimulatory effect of IL-18 in zoledronate-induced gd T cell expansion (33).…”

“…Although upstream accumulation of IPP during N-BP-mediated FPP synthase inhibition provides Ag for the specific stimulation of gd T cells, the downstream depletion of FPP and geranylgeranyl pyrophosphate (GGPP) was shown to generate cell stress and to translate into caspase-1-dependent inflammatory responses, both in vitro and in vivo (3,(28)(29)(30). IL-18, which is a stress-related, caspase-1-processed cytokine (31), was implicated in zoledronateinduced NK cell and gd T cell activation (29) and was shown to costimulate zoledronate-induced, IL-2-driven gd T cell expansion (32).…”

γδ-T cells: an unpolished sword in human anti-infection immunity

“…In addition to their direct anti-infection activities, human cd-T cells act as professional APCs and take up, process and present pathogen-related antigens from both free viral particles 29 and infected cells 57,105 to other effector immune cells. 106,107 These cd-T APCs express approximately similar levels of HLA-DR and CD80/ CD86 compared to traditional APCs 29 and induce NK cell activation, 108,109 antigen-specific ab-T-cell responses 29,107 and even antibody production. 67 Although the physiological roles of cd-T APCs still need to be illuminated by more in vivo studies, recent investigations of murine cd-T cells have confirmed the general existence of cd-T APCs.…”