Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation.
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)-beta 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-beta-dependent manner in mice and rats. Tumor cells are necessary and sufficient to convert DCs into regulatory cells that secrete bioactive TGF-beta and stimulate T reg cell proliferation. In conclusion, tumor expansion can stimulate T reg cells via a specific DC subset.
Ghiringhelli
François
F
Institut National de la Santé et de la Recherche Médicale, U517, University of Burgundy, 21079 Dijon, France.
Puig
Pierre E
PE
Roux
Stephan
S
Parcellier
Arnaud
A
Schmitt
Elise
E
Solary
Eric
E
Kroemer
Guido
G
Martin
François
F
Chauffert
Bruno
B
Zitvogel
Laurence
L
D000818:Animals; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017931:DNA Primers; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D051381:Rats; D011919:Rats, Inbred Strains; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
D017931:DNA Primers; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D001973:Bromodeoxyuridine