title: Inhibition of suppressive T cell factor 1 (TCF-1) isoforms in naive CD4+ T cells is mediated by IL-4/STAT6 signaling.
abstract: The Wnt pathway transcription factor T cell factor 1 (TCF-1) plays essential roles in the control of several developmental processes, including T cell development in the thymus. Although previously regarded as being required only during early T cell development, recent studies demonstrate an important role for TCF-1 in T helper 2 (Th2) cell polarization. TCF-1 was shown to activate expression of the Th2 transcription factor GATA-binding protein 3 (GATA3) and thus to promote the development of IL-4-producing Th2 cells independent of STAT6 signaling. In this study, we show that TCF-1 is down-regulated in human naive CD4(+) T cells cultured under Th2-polarizing conditions. The down-regulation is largely due to the polarizing cytokine IL-4 because IL-4 alone is sufficient to substantially inhibit TCF-1 expression. The IL-4-induced suppression of TCF-1 is mediated by STAT6, as shown by electrophoretic mobility shift assays, chromatin immunoprecipitation, and STAT6 knockdown experiments. Moreover, we found that IL-4/STAT6 predominantly inhibits the shorter, dominant-negative TCF-1 isoforms, which were reported to inhibit IL-4 transcription. Thus, this study provides a model for an IL-4/STAT6-dependent fine tuning mechanism of TCF-1-driven T helper cell polarization.
authors.affiliation: Department of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, A-5020 Salzburg, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Maier
authors.forename: Daniel
authors.initials: D
authors.lastname: Hebenstreit
authors.forename: Gernot
authors.initials: G
authors.lastname: Posselt
authors.forename: Peter
authors.initials: P
authors.lastname: Hammerl
authors.forename: Albert
authors.initials: A
authors.lastname: Duschl
authors.forename: Jutta
authors.initials: J
authors.lastname: Horejs-Hoeck
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016764:Cell Polarity / Q000276:immunology*; D002478:Cells, Cultured; D015870:Gene Expression / Q000276:immunology; D051538:Hepatocyte Nuclear Factor 1-alpha; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C508598:IL4 protein, human; C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; D015847:Interleukin-4