DNAX accessory molecule-1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vgamma9Vdelta2 T cells

Eur J Immunol. 2009 May;39(5):1361-8. doi: 10.1002/eji.200838409.


Human Vgamma9Vdelta2 T lymphocytes can be activated by nonpeptidic antigens such as the mevalonate pathway-derived isopentenyl pyrophosphate or synthetic phosphoantigen such as bromohydrin pyrophosphate. They display a strong cytotoxic activity against several tumor types, including hepatocellular carcinoma (HCC). Little is known about the mechanisms underlying Vgamma9Vdelta2 T-cell recognition of tumor cells, but there is strong evidence that activating NK receptors play a role in gammadelta T-cell cytotoxicity. In this study, we showed that the two NK receptors DNAX accessory molecule-1 (DNAM-1) and CD96 were expressed by Vgamma9Vdelta2 T cells. The ligands Nectin-like-5 specific of both DNAM-1 and CD96, and also Nectin-2, an additional ligand of DNAM-1, were present on all HCC cell lines analyzed. Furthermore, we demonstrated by mAb-mediated masking experiments that cytotoxicity against HCC cells as well as IFN-gamma production in gammadelta T cells were dependent on DNAM-1. Our experiments indicated that Nectin-like-5 but not Nectin-2 was involved in DNAM-1-dependent gammadelta T-cell functions. We did not reveal a role for CD96 in the killing of HCC cells. Finally, we showed by combined mAb-mediated blockade that DNAM-1 and NKG2D could cooperate in the cell lysis of HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Antigens, CD / biosynthesis
  • Antigens, CD / immunology
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis
  • Antigens, Differentiation, T-Lymphocyte / immunology*
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / therapy
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / immunology
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Flow Cytometry
  • Humans
  • Immunity, Innate / immunology
  • Immunotherapy / methods
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / therapy
  • Lymphocyte Activation
  • Nectins
  • RNA, Small Interfering / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • Receptors, Virus / genetics
  • Receptors, Virus / immunology
  • T-Lymphocytes / immunology*
  • Transfection


  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD226 antigen
  • CD96 antigen
  • Cell Adhesion Molecules
  • Nectins
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Virus
  • poliovirus receptor