Activated human gammadelta T cells as stimulators of specific CD8+ T-cell responses to subdominant Epstein Barr virus epitopes: potential for immunotherapy of cancer

J Immunother. 2009 Apr;32(3):310-21. doi: 10.1097/CJI.0b013e31819b7c30.

Abstract

The efficacy of current cancer vaccines is limited by the functional heterogeneity and poor availability and expansion of professional antigen-presenting cells (APCs). Besides their potent innate effector properties, gammadelta T cells have been suggested to be involved in the initiation and maintenance of adaptive immune responses. Here, we investigated the capacity of human gammadelta T cells to induce expansion of virus-specific T cells to Epstein Barr virus (EBV) antigens. Aminobisphosphonate-stimulated human peripheral blood-derived gammadelta T cells (Vgamma2+Vdelta2+) acquired a dual phenotype characteristic for both APCs and effector memory T cells. Coincubation of activated gammadelta T cells pulsed with human leukocyte antigen-restricted epitopes of either the highly stimulatory EBV lytic cycle antigen Bam H1 Z fragment leftward open reading frame or the tumor-associated latent EBV antigen latent membrane protein 2a (LMP2a) with autologous peripheral blood lymphocytes induced selective expansion of peptide-specific, fully functional CD3CD8 cytolytic effector memory T cells. Furthermore, gammadelta T APCs efficiently processed and presented endogenous antigen, as demonstrated by the capacity of LMP2a gene-transduced gammadelta T cells to induce expansion of T cells with broad specificity for various LMP2a peptides. The capacity of autologous gammadelta T cells to induce LMP2a-specific autologous cytotoxic T lymphocytes was confirmed in 2 patients with Hodgkin lymphoma. In summary, bisphosphonate-activated human gammadelta T cells stimulate expansion of cytotoxic effector T cells specific for both subdominant and dominant viral epitopes and thus show promise as a novel source of efficient APCs for immunotherapy of viral and malignant disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / virology
  • Antigens, Viral / immunology*
  • Antigens, Viral / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Diphosphonates / pharmacology
  • Epitopes / immunology*
  • Epitopes / metabolism
  • Epstein-Barr Virus Infections / therapy*
  • Herpesvirus 4, Human / immunology*
  • Humans
  • Imidazoles / pharmacology
  • Immunotherapy*
  • Receptors, Antigen, T-Cell, gamma-delta / drug effects
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Transduction, Genetic
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / immunology
  • Zoledronic Acid

Substances

  • Antigens, Viral
  • Diphosphonates
  • Epitopes
  • Imidazoles
  • Receptors, Antigen, T-Cell, gamma-delta
  • Tumor Necrosis Factor-alpha
  • Zoledronic Acid