title: Integrated T-cell receptor and costimulatory signals determine TGF-β-dependent differentiation and maintenance of Foxp3+ regulatory T cells.
abstract: Foxp3-expressing Tregs play a non-redundant role in protecting against immune pathologies. Foxp3(+) Tregs can arise intra- and extra-thymically, however, the signals directing their differentiation and maintenance in the periphery are not well understood. We show that stimulation of mouse naïve CD4(+) T cells in vitro with optimal doses of anti-CD3/anti-CD28 resulted in high frequencies of Foxp3(+) T cells via a TGF-β-dependent mechanism. Addition of TGF-β and retinoic acid overcame the inhibition of Foxp3 expression observed during high-strength anti-CD3/anti-CD28 stimulation. Reducing the strength of TCR or costimulatory signals with inhibitors of mammalian target of rapamycin (mTOR) or MEK/ERK signalling also enhanced expression of Foxp3 in a TGF-β-dependent manner. Addition of TGF-β was further required to maintain Foxp3 expression in ex vivo derived Foxp3(+) Tregs upon prolonged anti-CD3/anti-CD28 signalling. Thus, induction/maintenance of Foxp3 expression by TGF-β is modulated by the integrated strength of TCR/costimulatory signals.
authors.affiliation: Division of Immunoregulation, MRC National Institute for Medical Research, London, UK.
authors.forename: Leona
authors.initials: L
authors.lastname: Gabryšová
authors.forename: Jillian R
authors.initials: JR
authors.lastname: Christensen
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wu
authors.forename: Adrien
authors.initials: A
authors.lastname: Kissenpfennig
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.forename: Anne
authors.initials: A
authors.lastname: O'Garra
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; D018106:CD28 Antigens; D017252:CD3 Complex; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D014212:Tretinoin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases