title: Foxo transcription factors control regulatory T cell development and function.
abstract: Foxo transcription factors integrate extrinsic signals to regulate cell division, differentiation and survival, and specific functions of lymphoid and myeloid cells. Here, we showed the absence of Foxo1 severely curtailed the development of Foxp3(+) regulatory T (Treg) cells and those that developed were nonfunctional in vivo. The loss of function included diminished CTLA-4 receptor expression as the Ctla4 gene was a direct target of Foxo1. T cell-specific loss of Foxo1 resulted in exocrine pancreatitis, hind limb paralysis, multiorgan lymphocyte infiltration, anti-nuclear antibodies and expanded germinal centers. Foxo-mediated control over Treg cell specification was further revealed by the inability of TGF-β cytokine to suppress T-bet transcription factor in the absence of Foxo1, resulting in IFN-γ secretion. In addition, the absence of Foxo3 exacerbated the effects of the loss of Foxo1. Thus, Foxo transcription factors guide the contingencies of T cell differentiation and the specific functions of effector cell populations.
authors.affiliation: Molecular Biology Section, Division of Biological Sciences and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0377, USA.
authors.forename: Yann M
authors.initials: YM
authors.lastname: Kerdiles
authors.forename: Erica L
authors.initials: EL
authors.lastname: Stone
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Beisner
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Beisner
authors.forename: Maureen A
authors.initials: MA
authors.lastname: McGargill
authors.forename: Irene L
authors.initials: IL
authors.lastname: Ch'en
authors.forename: Christian
authors.initials: C
authors.lastname: Stockmann
authors.forename: Carol D
authors.initials: CD
authors.lastname: Katayama
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hedrick
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics; D060908:CTLA-4 Antigen; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058408:Th1-Th2 Balance; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C498833:Foxp3 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016212:Transforming Growth Factor beta