Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7.
CD4(+)CD25(+) regulatory cells are a subpopulation of T lymphocytes of thymic origin. However, recent data suggest an alternative commitment of regulatory T cells in the periphery, although the precise mechanism is unknown. In the present work, we demonstrate that TGF-beta is able to induce Foxp3 expression and subsequently a regulatory phenotype in CD4(+)CD25(-) peripheral murine T cells. Similarly, TGF-beta induced Foxp3 in human CD4(+)CD25(-) T cells. Moreover, we show that the inhibitory Smad7 protein that is normally induced by TGF-beta and limits TGF-beta signaling, is strongly down-regulated by Foxp3 at the transcriptional level. Foxp3-mediated down-regulation of Smad7 subsequently rendered CD4(+)CD25(-) T cells highly susceptible to the morphogenic and regulatory effects of TGF-beta signaling via Smad3/4. In summary, we demonstrate that TGF-beta induces a regulatory phenotype in CD4(+)CD25(-) T cells through the induction of Foxp3 and a positive autoregulatory loop of TGF-beta signaling due to the absence of Smad7.
Fantini
Massimo C
MC
Laboratory of Immunology, I. Medical Clinic, Johannes Gutenberg University of Mainz, Mainz, Germany.
Becker
Christoph
C
Monteleone
Giovanni
G
Pallone
Francesco
F
Galle
Peter R
PR
Neurath
Markus F
MF
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology*; D051858:Forkhead Transcription Factors; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051906:Smad7 Protein; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*
D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015375:Receptors, Interleukin-2; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta