title: Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3.
abstract: The transcription factor Foxp3 dominantly controls regulatory T (Treg) cell function, and only its continuous expression guarantees the maintenance of full Treg cell-suppressive capacity. However, transcriptional regulators maintaining Foxp3 transcription are incompletely described. Here, we report that high E47 transcription factor activity in Treg cells resulted in unstable Foxp3 expression. Under homeostatic conditions, Treg cells expressed high levels of the E47 antagonist Id3, thus restricting E47 activity and maintaining Foxp3 expression. In contrast, stimulation of Id3-deficient or E47-overexpressing Treg cells resulted in the loss of Foxp3 expression in a subset of Treg cells in vivo and in vitro. Mechanistic analysis indicated that E47 activated expression of the transcription factor Spi-B and the suppressor of cytokine signaling 3 (SOCS3), which both downregulated Foxp3 expression. These findings demonstrate that the balance of Id3 and E47 controls the maintenance of Foxp3 expression in Treg cells and, thus, contributes to Treg cell plasticity.
authors.affiliation: Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Rauch
authors.affiliation: Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Hils
authors.affiliation: Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Lupar
authors.affiliation: Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Susana
authors.initials: S
authors.lastname: Minguet
authors.affiliation: Institution for Clinical and Experimental Sciences, Faculty of Health Sciences, Linköping University, 58183 Linköping, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Rottenberg
authors.affiliation: Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany; Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Izcue
authors.affiliation: Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schachtrup
authors.affiliation: Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany. Electronic address: kristina.schachtrup@uniklinik-freiburg.de.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schachtrup
mesh_terms: D000818:Animals; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics*; D051379:Mice; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D058127:Transcription Factor 3 / Q000235:genetics*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051796:Inhibitor of Differentiation Proteins; D050783:Proto-Oncogene Proteins c-ets; C514177:Spi-B protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D058127:Transcription Factor 3; C067679:Idb3 protein, mouse
keywords: E2A; Foxp3 stability; Treg cells; colitis; enhancer; transcription