The Journal of Experimental Medicine
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Published online 26 September 2005 doi:10.1084/jem.20050463
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 7, 919-929
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ARTICLE

 Tumor cells convert immature myeloid dendritic cells into TGF-ß–secreting cells inducing CD4+CD25+ regulatory T cell proliferation

François Ghiringhelli1, Pierre E. Puig1, Stephan Roux2, Arnaud Parcellier1, Elise Schmitt1, Eric Solary1, Guido Kroemer3, François Martin1, Bruno Chauffert1, and Laurence Zitvogel2

1 Institut National de la Santé et de la Recherche Médicale, U517, University of Burgundy, 21079 Dijon, France
2 ERM 0208, Institut National de la Santé et de la Recherche Médicale
3 UMR 8125, Centre National de la Recherche Scientifique, Institut Gustave Roussy, 94805 Villejuif, France

CORRESPONDENCE Laurence Zitvogel: zitvogel{at}igr.fr OR Bruno Chauffert: Bchauffert{at}dijon.fnclcc.fr

The mechanisms through which regulatory T cells accumulate in lymphoid organs of tumor-bearing hosts remain elusive. Our experiments indicate that the accumulation of CD4+CD25+ regulatory T cells (T reg cells) expressing FoxP3 and exhibiting immunosuppressive function originates from the proliferation of naturally occurring CD25+ T cells and requires signaling through transforming growth factor (TGF)–ß receptor II. During tumor progression, a subset of dendritic cells (DCs) exhibiting a myeloid immature phenotype is recruited to draining lymph nodes. This DC subset selectively promotes the proliferation of T reg cells in a TGF-ß–dependent manner in mice and rats. Tumor cells are necessary and sufficient to convert DCs into regulatory cells that secrete bioactive TGF-ß and stimulate T reg cell proliferation. In conclusion, tumor expansion can stimulate T reg cells via a specific DC subset.

Abbreviations used: BrdU, 5-bromo-2'-deoxyuridine; CFSE, carboxyfluorescein diacetate succinimidyl ester; ConA, concanavalin A; DLN, draining LN; DN TGF-ßRII mice, dominant-negative TGF-ß receptor II–signaling mice bearing transgenic T cells; IMDC, immature myeloid DC; TBM, tumor-bearing mice; TBR, tumor-bearing rats; TFM, tumor-free mouse/mice; TFR, tumor-free rats; T reg cells, CD4+CD25+ regulatory T cells.

B. Chauffert and L. Zitvogel contributed equally to this work.


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