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

Blood. 2011 Sep 8;118(10):2743-51. doi: 10.1182/blood-2011-01-328526. Epub 2011 Jun 14.


Bisphosphonates are mainly used for the inhibition of osteoclast-mediated bone resorption but also have been shown to induce γδ T-cell activation. Using IL-2-primed cultures of CD56(+) peripheral blood mononuclear cells, we show here that zoledronic acid (zoledronate) could induce IFN-γ production not only in γδ 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 γδ T lymphocytes, DC-like cells were rapidly eliminated, and NK cell IFN-γ production was silenced. Conversely, in the absence of γδ T lymphocytes, DC-like cells were spared, allowing NK cell IFN-γ production to proceed. γδ 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-1β for the activation of IL-2-primed NK cells. Pharmacologic inhibition of caspase-1 almost abolished IFN-γ production in NK cells and γδ T lymphocytes, indicating that caspase-1-mediated cytokine maturation is the crucial mechanism underlying innate lymphocyte activation in response to zoledronate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Presenting Cells / drug effects
  • Antigen-Presenting Cells / immunology*
  • Antigen-Presenting Cells / metabolism
  • Bone Density Conservation Agents / pharmacology
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Diphosphonates / pharmacology*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Imidazoles / pharmacology*
  • Immunomagnetic Separation
  • Interferon-gamma / metabolism
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-2 / metabolism
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Leukocytes, Mononuclear
  • Lymphocyte Activation / drug effects*
  • Pamidronate
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Zoledronic Acid


  • Bone Density Conservation Agents
  • Diphosphonates
  • Imidazoles
  • Interleukin-18
  • Interleukin-1beta
  • Interleukin-2
  • Receptors, Antigen, T-Cell, gamma-delta
  • Zoledronic Acid
  • Interferon-gamma
  • Caspase 1
  • Pamidronate