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)–β 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-β–dependent manner in mice and rats. Tumor cells are necessary and sufficient to convert DCs into regulatory cells that secrete bioactive TGF-β and stimulate T reg cell proliferation. In conclusion, tumor expansion can stimulate T reg cells via a specific DC subset.
Tumor cells convert immature myeloid dendritic cells into TGF-β–secreting cells inducing CD4 + CD25 + regulatory T cell proliferation
Abbreviations used: BrdU, 5-bromo-2′-deoxyuridine; CFSE, carboxyfluorescein diacetate succinimidyl ester; ConA, concanavalin A; DLN, draining LN; DN TGF-βRII mice, dominant-negative TGF-β 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.
François Ghiringhelli, Pierre E. Puig, Stephan Roux, Arnaud Parcellier, Elise Schmitt, Eric Solary, Guido Kroemer, François Martin, Bruno Chauffert, Laurence Zitvogel; Tumor cells convert immature myeloid dendritic cells into TGF-β–secreting cells inducing CD4+CD25+ regulatory T cell proliferation . J Exp Med 3 October 2005; 202 (7): 919–929. doi: https://doi.org/10.1084/jem.20050463
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