Human dendritic cells produce TGF-beta 1 under the influence of lung carcinoma cells and prime the differentiation of CD4+CD25+Foxp3+ regulatory T cells.
Dendritic cells (DCs) have a central role in the development of adaptive immune responses, including antitumor immunity. Factors present in the tumor milieu can alter the maturation of DCs and inhibit their capacity to activate T cells. Using gene expression analysis, we found that human DCs increased the expression of TGF-beta1 transcripts following culture with human lung carcinoma cells (LCCs). These DCs produced increased amounts of TGF-beta1 protein compared with DCs not exposed to tumor cells. LCCs also decreased the expression of CD86 and HLA-DR by immature DCs. Furthermore, LCCs decreased CD86 expression and the production of TNF-alpha and IL-12 p70 by mature DCs. Moreover, LCCs also converted mature DCs into cells producing TGF-beta1. These TGF-beta1-producing DCs were poor at eliciting the activation of naive CD4(+) T cells and sustaining their proliferation and differentiation into Th1 (IFN-gamma(+)) effectors. Instead, TGF-beta1-producing DCs demonstrated an increased ability to generate CD4(+)CD25(+)Foxp3(+) regulatory T cells that suppress the proliferation of T lymphocytes. These results identify a novel mechanism by which the function of human DCs is altered by tumor cells and contributes to the evasion of the immune response.
Dumitriu
Ingrid E
IE
Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. i.dumitriu@sgul.ac.uk
Dunbar
Donald R
DR
Howie
Sarah E
SE
Sethi
Tariq
T
Gregory
Christopher D
CD
D051940:B7-2 Antigen / Q000096:biosynthesis / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D051940:B7-2 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12