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.
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.
Lin
Chun-Ming
CM
Department of Microbiology, Soochow University, Wai Shuang Hsi, Shih Lin, Taipei, Taiwan 11102, Republic of China. yclin@mail.scu.edu.tw
Wang
Fu-Hwei
FH
Lee
Pao-Kung
PK
D017951:Antigen Presentation; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D017635:Clonal Anergy / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000494:pharmacology
D018106:CD28 Antigens; D017252:CD3 Complex; D016212:Transforming Growth Factor beta