title: Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency.
abstract: Regulatory T (Treg) cells, driven by the Foxp3 transcription factor, are responsible for limiting autoimmunity and chronic inflammation. We showed that a well-characterized Foxp3(gfp) reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg cell development and in vitro function are not markedly altered in Foxp3(gfp) NOD and C57BL/6 mice, Treg cell function in inflammatory environments was perturbed and TGF-β-induced Treg cell development was reduced. Foxp3(gfp) was unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which led to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this results in an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg cell insufficiency that enables autoimmunity in susceptible environments.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Bettini
authors.forename: Fan
authors.initials: F
authors.lastname: Pan
authors.forename: Maria
authors.initials: M
authors.lastname: Bettini
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Stefan
authors.initials: S
authors.lastname: Floess
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Bell
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D000107:Acetylation; D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C118760:Zfpn1a4 protein, mouse; D051548:Histone Acetyltransferases; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases