Copulsing tumor antigen-pulsed dendritic cells with zoledronate efficiently enhance the expansion of tumor antigen-specific CD8+ T cells via Vgamma9gammadelta T cell activation

J Leukoc Biol. 2008 Mar;83(3):742-54. doi: 10.1189/jlb.0307185. Epub 2007 Dec 21.

Abstract

We demonstrate that Vgamma9gammadelta T cells activated by zoledronate can link innate and acquired immunity through crosstalk with dendritic cells (DCs) in a way that can amplify activation and proliferation of tumor antigen-specific CD8+ T cells. DCs pulsed with antigen alone or antigen plus zoledronate were used to stimulate the in vitro expansion of antigen-specific CD8+ T cells. MART-1-modified peptide (A27L peptide) and apoptotic HLA-A*0201-positive, MART-1-positive JCOCB tumor cell lines were used as tumor antigen sources. The percentage of A27L-specific CD8+ T cells within the responding lymphocytes on Day 7 when immature DCs (imDCs) were cultured in the presence of A27L peptide and 0.01 microM zoledronate was significantly higher (P=0.002, n=11) than that observed when imDCs were cultured with the lymphocytes in the presence of the A27L peptide alone. This enhancing effect of zoledronate was significantly reduced when gammadelta T cells were depleted from responding lymphocytes (P=0.030, n=5), indicating that the effect is mediated mainly through Vgamma9gammadelta T cells activated by zoledronate-pulsed imDCs. When imDCs copulsed with zoledronate and apoptotic JCOCB tumor cell lines were used, the percentage of A27L-specific CD8+ T cells was higher than that observed using imDCs with the apoptotic JCOCB lines alone, suggesting that zoledronate treatment of imDCs enhances the cross-presentation ability of DCs. These findings suggest a potentially valuable role for Vgamma9gammadelta T cell activation for expanding antigen-specific CD8+T cells using DCs copulsed with tumor antigen and zoledronate in the design of vaccine therapies for malignancy.

MeSH terms

  • Antibodies, Monoclonal
  • Antigens, Neoplasm / immunology*
  • Bone Density Conservation Agents / pharmacology
  • CD8 Antigens / immunology
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Culture Techniques
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Diphosphonates / pharmacology*
  • Humans
  • Imidazoles / pharmacology*
  • Lymphocyte Activation / drug effects*
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • Zoledronic Acid

Substances

  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • Bone Density Conservation Agents
  • CD8 Antigens
  • Diphosphonates
  • Imidazoles
  • Receptors, Antigen, T-Cell, gamma-delta
  • Zoledronic Acid