title: Agonist-driven development of CD4+CD25+Foxp3+ regulatory T cells requires a second signal mediated by Stat6.
abstract: The factors that induce Foxp3 expression and regulatory T (Treg) cell development remain unknown. In this study, we investigated the role of STAT4 and STAT6 in agonist-driven generation of Ag-specific Foxp3-expressing Treg cells. Our findings indicate that fully efficient induction of Foxp3 expression and development of Ag-specific Treg cells requires the synergistic action of two signals: a TCR-mediated signal and a second signal mediated by STAT6. Indeed, by comparing the development of wild-type and STAT4- and STAT6-deficient hemagglutinin-specific T cells in the presence of hemagglutinin Ag, we found that the absence of STAT6 impaired the generation of Ag-specific CD4+CD25+Foxp3+ cells. Moreover, in transgenic mice expressing a constitutively active form of STAT6, we found that the fraction of CD4+Foxp3+ cells exceeds that of control wild-type littermates. Overall these findings support a role for the STAT6 pathway in Treg cell development and maintenance.
authors.affiliation: Unité de Biologie des Populations Lymphocytaires, Centre National de la Recherche Scientifique, Institut Pasteur, 25 rue du Dr. Roux, 75015 Paris, France.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Sanchez-Guajardo
authors.forename: Corinne
authors.initials: C
authors.lastname: Tanchot
authors.forename: John T
authors.initials: JT
authors.lastname: O'Malley
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garcia
authors.forename: Antonio A
authors.initials: AA
authors.lastname: Freitas
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000378:metabolism*; D006388:Hemagglutinins / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*
chemical_list: D000941:Antigens; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006388:Hemagglutinins; D053645:Interleukin-2 Receptor alpha Subunit; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse