title: Dynamic changes in E-protein activity regulate T reg cell development.
abstract: E-proteins are TCR-sensitive transcription factors essential for intrathymic T cell transitions. Here, we show that deletion of E-proteins leads to both enhanced peripheral TGF-β-induced regulatory T (iT reg) cell and thymic naturally arising T reg cell (nT reg cell) differentiation. In contrast, deletion of Id proteins results in reduced nT reg cell differentiation. Mechanistic analysis indicated that decreased E-protein activity leads to de-repression of signaling pathways that are essential to Foxp3 expression. Decreased E-protein binding to an IL-2Rα enhancer locus facilitated TCR-induced IL-2Rα expression. Similarly, decreased E-protein activity facilitated TCR-induced NF-κB activation and generation of c-Rel. Consistent with this, microarray analysis indicated that cells with E-protein depletion that are not yet expressing Foxp3 exhibit activation of the IL-2 and NF-κB signaling pathways as well as enhanced expression of many of the genes associated with Foxp3 induction. Finally, studies using Nur77-GFP mice to monitor TCR signaling showed that TCR signaling strength sufficient to induce Foxp3 differentiation is accompanied by down-regulation of E-protein levels. Collectively, these data suggest that TCR stimulation acts in part through down-regulation of E-protein activity to induce T reg cell lineage development.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Han
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses; Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Zhiqiong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses; Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Ivan J
authors.initials: IJ
authors.lastname: Fuss
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses; Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Myers
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses; Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gardina
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China zhangfp@im.ac.cn wstrober@niaid.nih.gov.
authors.forename: Fuping
authors.initials: F
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China Mucosal Immunity Section, Laboratory of Host Defenses; Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 zhangfp@im.ac.cn wstrober@niaid.nih.gov.
authors.forename: Warren
authors.initials: W
authors.lastname: Strober
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; D051796:Inhibitor of Differentiation Proteins; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; C498833:Foxp3 protein, mouse