title: IL-1β promotes Th17 differentiation by inducing alternative splicing of FOXP3.
abstract: CD4(+)FOXP3(+) regulatory T (Treg) cells are essential for maintaining immunological self-tolerance. Treg cell development and function depend on the transcription factor FOXP3, which is present in several distinct isoforms due to alternative splicing. Despite the importance of FOXP3 in the proper maintenance of Treg cells, the regulation and functional consequences of FOXP3 isoform expression remains poorly understood. Here, we show that in human Treg cells IL-1β promotes excision of FOXP3 exon 7. FOXP3 is not only expressed by Treg cells but is also transiently expressed when naïve T cells differentiate into Th17 cells. Forced splicing of FOXP3 into FOXP3Δ2Δ7 strongly favored Th17 differentiation in vitro. We also found that patients with Crohn's disease express increased levels of FOXP3 transcripts lacking exon 7, which correlate with disease severity and IL-17 production. Our results demonstrate that alternative splicing of FOXP3 modulates T cell differentiation. These results highlight the importance of characterizing FOXP3 expression on an isoform basis and suggest that immune responses may be manipulated by modulating the expression of FOXP3 isoforms, which has broad implications for the treatment of autoimmune diseases.
authors.affiliation: Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Reiner K W
authors.initials: RK
authors.lastname: Mailer
authors.affiliation: Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Joly
authors.affiliation: Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Unit of Computational Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Elias
authors.affiliation: Unit of Computational Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegner
authors.affiliation: Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Andersson
mesh_terms: D017398:Alternative Splicing; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D020381:Interleukin-17 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D008213:Lymphocyte Activation; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D053583:Interleukin-1beta; D020033:Protein Isoforms; D012333:RNA, Messenger