title: IFN regulatory factor-1 negatively regulates CD4+ CD25+ regulatory T cell differentiation by repressing Foxp3 expression.
abstract: Regulatory T (Treg) cells are critical in inducing and maintaining tolerance. Despite progress in understanding the basis of immune tolerance, mechanisms and molecules involved in the generation of Treg cells remain poorly understood. IFN regulatory factor (IRF)-1 is a pleiotropic transcription factor implicated in the regulation of various immune processes. In this study, we report that IRF-1 negatively regulates CD4(+)CD25(+) Treg cell development and function by specifically repressing Foxp3 expression. IRF-1-deficient (IRF-1(-/-)) mice showed a selective and marked increase of highly activated and differentiated CD4(+)CD25(+)Foxp3(+) Treg cells in thymus and in all peripheral lymphoid organs. Furthermore, IRF-1(-/-) CD4(+)CD25(-) T cells showed extremely high bent to differentiate into CD4(+)CD25(+)Foxp3(+) Treg cells, whereas restoring IRF-1 expression in IRF-1(-/-) CD4(+)CD25(-) T cells impaired their differentiation into CD25(+)Foxp3(+) cells. Functionally, both isolated and TGF-beta-induced CD4(+)CD25(+) Treg cells from IRF-1(-/-) mice exhibited more increased suppressive activity than wild-type Treg cells. Such phenotype and functional characteristics were explained at a mechanistic level by the finding that IRF-1 binds a highly conserved IRF consensus element sequence (IRF-E) in the foxp3 gene promoter in vivo and negatively regulates its transcriptional activity. We conclude that IRF-1 is a key negative regulator of CD4(+)CD25(+) Treg cells through direct repression of Foxp3 expression.
authors.affiliation: Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fragale
authors.forename: Lucia
authors.initials: L
authors.lastname: Gabriele
authors.forename: Emilia
authors.initials: E
authors.lastname: Stellacci
authors.forename: Paola
authors.initials: P
authors.lastname: Borghi
authors.forename: Edvige
authors.initials: E
authors.lastname: Perrotti
authors.forename: Ramona
authors.initials: R
authors.lastname: Ilari
authors.forename: Angela
authors.initials: A
authors.lastname: Lanciotti
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Remoli
authors.forename: Massimo
authors.initials: M
authors.lastname: Venditti
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.forename: Angela
authors.initials: A
authors.lastname: Battistini
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D016384:Consensus Sequence; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050856:Interferon Regulatory Factor-1; D053645:Interleukin-2 Receptor alpha Subunit