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Human Dendritic Cells Produce TGF-β1 under the Influence of Lung Carcinoma Cells and Prime the Differentiation of CD4⁺CD25⁺Foxp3⁺ Regulatory T Cells¹

Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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-β1 transcripts following culture with human lung carcinoma cells (LCCs). These DCs produced increased amounts of TGF-β1 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- and IL-12 p70 by mature DCs. Moreover, LCCs also converted mature DCs into cells producing TGF-β1. These TGF-β1-producing DCs were poor at eliciting the activation of naive CD4⁺ T cells and sustaining their proliferation and differentiation into Th1 (IFN-⁺) effectors. Instead, TGF-β1-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Norman Salvesen Emphysema Research Trust (to I.E.D. (principal investigator), C.D.G. (co-principle investigator), and T.S. (co-principal investigator)) and St. George’s Hospital London Charitable Foundation (to I.E.D. (PI)). D.R.D. is funded by the Wellcome Trust’s Functional Genomics Development Initiative and Cardiovascular Research Initiative.

I.E.D. defined the experimental strategy, designed and performed experiments, analyzed data, and wrote the manuscript. D.D. contributed to the design of the microarray gene expression experiments and analyzed the data obtained in the microarray profiling. S.E.H. and T.S. provided vital reagents and critical discussion. C.D.G. defined the experimental strategy and wrote the manuscript.

² Address correspondence and reprint requests to Dr. Ingrid E. Dumitriu at the current address: Division of Cardiac and Vascular Sciences, St. George’s University of London, Cranmer Terrace, SW17 0RE, London, U.K. E-mail address: i.dumitriu{at}sgul.ac.uk

³ Abbreviations used in this paper: DC, dendritic cell; LCC, lung carcinoma cell line; VEGF, vascular endothelial growth factor; LAP, latency-associated peptide; iDC, immature DC; mDC, mature DC; MFI, mean fluorescence intensity; w/o, without.