Inhibition of phosphoantigen-mediated gammadelta T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells

Immunology. 2009 Feb;126(2):256-67. doi: 10.1111/j.1365-2567.2008.02894.x. Epub 2008 Sep 2.


Tumour growth promotes the expansion of CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) which suppress various arms of immune responses and might therefore contribute to tumour immunosurveillance. In this study, we found an inverse correlation between circulating Treg frequencies and phosphoantigen-induced gammadelta T-cell proliferation in cancer patients, which prompted us to address the role of Tregs in controlling the gammadelta T-cell arm of innate immune responses. In vitro, human Treg-peripheral blood mononuclear cell (PBMC) co-cultures strongly inhibited phosphoantigen-induced proliferation of gammadelta T cells and depletion of Tregs restored the impaired phosphoantigen-induced gammadelta T-cell proliferation of cancer patients. Tregs did not suppress other effector functions of gammadelta T cells such as cytokine production or cytotoxicity. Our experiments indicate that Tregs do not mediate their suppressive activity via a cell-cell contact-dependent mechanism, but rather secrete a soluble non-proteinaceous factor, which is independent of known soluble factors interacting with amino acid depletion (e.g. arginase-diminished arginine and indolamine 2,3-dioxygenase-diminished tryptophan) or nitric oxide (NO) production. However, the proliferative activity of alphabeta T cells was not affected by this cell-cell contact-independent suppressive activity induced by Tregs. In conclusion, these findings indicate a potential new mechanism by which Tregs can specifically suppress gammadelta T cells and highlight the strategy of combining Treg inhibition with subsequent gammadelta T-cell activation to enhance gammadelta T cell-mediated immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens / immunology
  • Cell Communication / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Cytotoxicity, Immunologic
  • Diphosphates
  • Forkhead Transcription Factors / analysis
  • Humans
  • Immune Tolerance / immunology
  • Immunity, Innate
  • Interleukin-2 Receptor alpha Subunit / analysis
  • Lymphocyte Culture Test, Mixed
  • Neoplasms / immunology*
  • Phosphoproteins / immunology*
  • Receptors, Antigen, T-Cell, gamma-delta / analysis
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Cells, Cultured


  • Antigens
  • Diphosphates
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2 Receptor alpha Subunit
  • Phosphoproteins
  • Receptors, Antigen, T-Cell, gamma-delta
  • bromohydrin pyrophosphate