title: The transcription factor musculin promotes the unidirectional development of peripheral Tregcells by suppressing the TH2 transcriptional program.
abstract: Although master transcription factors (TFs) are key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress the development of other, non-specific T cell lineages has not been fully elucidated. Through the use of regulatory T cells (Tregcells) induced by transforming growth factor-β (TGF-β), we identified the TF musculin (MSC) as being critical for the development of induced Tregcells (iTregcells) by repression of the T helper type 2 (TH2) transcriptional program. Loss of MSC reduced expression of the Tregcell master TF Foxp3 and induced TH2 differentiation even under iTreg-cell-differentiation conditions. MSC interrupted binding of the TF GATA-3 to the locus encoding TH2-cell-related cytokines and diminished intrachromosomal interactions within that locus. MSC-deficient (Msc-/-) iTregcells were unable to suppress TH2 responses, and Msc-/-mice spontaneously developed gut and lung inflammation with age. MSC therefore enforced Foxp3 expression and promoted the unidirectional induction of iTregcells by repressing the TH2 developmental program.
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Zuojia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Dardalhon
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Thalhamer
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mengyang
authors.initials: M
authors.lastname: Liao
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Asaf
authors.initials: A
authors.lastname: Madi
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Franca
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Han
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Oukka
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Kuchroo
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C498833:Foxp3 protein, mouse; C494748:Gata3 protein, mouse; C117673:Msc protein, mouse