title: Nuclear factor of activated T cells regulates the expression of interleukin-4 in Th2 cells in an all-or-none fashion.
abstract: Th2 memory lymphocytes have imprinted their Il4 genes epigenetically for expression in dependence of T cell receptor restimulation. However, in a given restimulation, not all Th cells with a memory for IL-4 expression express IL-4. Here, we show that in reactivated Th2 cells, the transcription factors NFATc2, NF-kB p65, c-Maf, p300, Brg1, STAT6, and GATA-3 assemble at the Il4 promoter in Th2 cells expressing IL-4 but not in Th2 cells not expressing it. NFATc2 is critical for assembly of this transcription factor complex. Because NFATc2 translocation into the nucleus occurs in an all-or-none fashion, dependent on complete dephosphorylation by calcineurin, NFATc2 controls the frequencies of cells reexpressing Il4, translates analog differences in T cell receptor stimulation into a digital decision for Il4 reexpression, and instructs all reexpressing cells to express the same amount of IL-4. This analog-to-digital conversion may be critical for the immune system to respond to low concentrations of antigens.
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Juliana
authors.initials: J
authors.lastname: Köck
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kreher
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Lehmann
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Riedel
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bardua
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Lischke
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Manja
authors.initials: M
authors.lastname: Jargosch
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Haftmann
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bendfeldt
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Hatam
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Mir-Farzin
authors.initials: MF
authors.lastname: Mashreghi
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Ria
authors.initials: R
authors.lastname: Baumgrass
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: German Rheumatism Research Center Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: chang@drfz.de.
authors.forename: Hyun-Dong
authors.initials: HD
authors.lastname: Chang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020218:Response Elements / Q000502:physiology*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C551587:Cmip protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; C498144:Rela protein, mouse; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors; D015847:Interleukin-4; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: Calcineurin; Cytokine; NFAT Transcription Factor; T-cell; T-cell Receptor (TCR)