Activated iNKT cells promote Vγ9Vδ2-T cell anti-tumor effector functions through the production of TNF-α

Clin Immunol. 2012 Feb;142(2):194-200. doi: 10.1016/j.clim.2011.10.006. Epub 2011 Nov 4.


Vγ9Vδ2-T cells constitute a proinflammatory lymphocyte subpopulation with established antitumor activity. Phosphoantigens activate Vγ9Vδ2-T cells in vivo and in vitro. We studied whether the antitumor activity of Vγ9Vδ2-T cells can be potentiated by invariant NKT cells (iNKT), an important immunoregulatory T cell subset. When activated by the glycolipid α-galactosylceramide (α-GalCer), iNKT produce large amounts of cytokines involved in antitumor immune responses. Monocyte-derived dendritic cells were loaded with both phosphoantigens (using aminobisphosphonates) and α-GalCer during maturation and subsequently co-cultured with Vγ9Vδ2-T and iNKT cells. Aminobisphosphonates dose-dependently enhanced Vγ9Vδ2-T cell activation, and this was potentiated by α-GalCer-induced iNKT co-activation. iNKT co-activation also enhanced the IFN-γ production and cytolytic potential of Vγ9Vδ2-T cells against tumor cells. Using transwell experiments and neutralizing antibodies cross-talk between iNKT and Vγ9Vδ2-T cells was found to be mediated by TNF-α. Our data provide a rationale for combining both activating ligands to improve Vγ9Vδ2-T cell based approaches in cancer-immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / immunology
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Diphosphonates / pharmacology
  • Galactosylceramides / immunology
  • Galactosylceramides / pharmacology
  • Hemiterpenes / metabolism
  • Humans
  • Immunologic Factors / immunology
  • Immunotherapy / methods
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Lymphocyte Activation / immunology*
  • Natural Killer T-Cells* / immunology
  • Natural Killer T-Cells* / metabolism
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Organophosphorus Compounds / metabolism
  • T-Lymphocytes, Cytotoxic* / immunology
  • T-Lymphocytes, Cytotoxic* / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / immunology


  • Antigens, Neoplasm
  • Diphosphonates
  • Galactosylceramides
  • Hemiterpenes
  • Immunologic Factors
  • Organophosphorus Compounds
  • Tumor Necrosis Factor-alpha
  • alpha-galactosylceramide
  • isopentenyl pyrophosphate
  • Interferon-gamma