Activated Human CD4+ T Cells Induced by Dendritic Cell Stimulation Are Most Sensitive to Transforming Growth Factor-β: Implications for Dendritic Cell Immunization against Cancer

The secretion of immunosuppressive factors like transforming growth factor-β (TGF-β) 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-β-induced immunosuppression by simulating the in vivo interaction among infused DCs, host T cells, and tumor-secreted TGF-β in an in vitro study. We found that both immature and mature DCs were relatively resistant to TGF-β. The addition of TGF-β 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-β, CD4+ T cells displayed a reduced capacity to proliferate. More importantly, activated CD4+ T cells induced by DC stimulation were very sensitive to TGF-β, and this susceptibility was enhanced by their previous exposure to TGF-β. The underlying mechanism was linked to TGF-β-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-β on activated CD4+ T cells. Taken together, our results indicate that the efficacy of DC immunization may be impaired by tumor-derived TGF-β.