Activated human CD4+ T cells induced by dendritic cell stimulation are most sensitive to transforming growth factor-beta: implications for dendritic cell immunization against cancer

Clin Immunol. 2002 Jan;102(1):96-105. doi: 10.1006/clim.2001.5151.

Abstract

The secretion of immunosuppressive factors like transforming growth factor-beta (TGF-beta) by tumor cells has been recognized as one of the mechanisms involved in tumor immunological escape. This study aimed to examine whether dendritic cell (DC) immunization could reverse TGF-beta-induced immunosuppression by simulating the in vivo interaction among infused DCs, host T cells, and tumor-secreted TGF-beta in an in vitro study. We found that both immature and mature DCs were relatively resistant to TGF-beta. The addition of TGF-beta to naive human CD4+ T cells, which are required by genetically modified DC to elicit antitumor immunity, resulted in their hyporesponsiveness to DC stimulation in a dose-dependent manner. When activated by allogeneic DCs in the presence of TGF-beta, CD4+ T cells displayed a reduced capacity to proliferate. More importantly, activated CD4+ T cells induced by DC stimulation were very sensitive to TGF-beta, and this susceptibility was enhanced by their previous exposure to TGF-beta. The underlying mechanism was linked to TGF-beta-induced apoptosis of activated T cells. However, the presence of stimulation from DC or antibodies to CD3 plus CD28 could partly reverse the immunosuppressive effect of TGF-beta on activated CD4+ T cells. Taken together, our results indicate that the efficacy of DC immunization may be impaired by tumor-derived TGF-beta.

MeSH terms

  • Antigen Presentation
  • CD28 Antigens / immunology
  • CD3 Complex / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation
  • Clonal Anergy / immunology
  • Dendritic Cells / immunology*
  • Humans
  • Immune Tolerance / immunology*
  • Lymphocyte Activation / drug effects
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Transforming Growth Factor beta / immunology*
  • Transforming Growth Factor beta / pharmacology

Substances

  • CD28 Antigens
  • CD3 Complex
  • Transforming Growth Factor beta