title: Tle4 regulates epigenetic silencing of gamma interferon expression during effector T helper cell tolerance.
abstract: In response to suboptimal activation, T cells become hyporesponsive, with a severely reduced capacity to proliferate and produce cytokines upon reencounter with antigen. Chromatin analysis of T cells made tolerant by use of different in vitro and in vivo approaches reveals that the expression of gamma interferon (IFN-γ) is epigenetically silenced in anergic effector TH1 cells. In those T cells, calcium signaling triggers the expression of Tle4, a member of the Groucho family of corepressors, which is then recruited to a distal regulatory element in the Ifng locus and causes the establishment of repressive epigenetic marks at the Ifng gene regulatory elements. Consequently, impaired Tle4 activity results in a markedly reduced capacity to inhibit IFN-γ production in tolerized T cells. We propose that Blimp1-dependent recruitment of Tle4 to the Ifng locus causes epigenetic silencing of the expression of the Ifng gene in anergic TH1 cells. These results define a novel function of Groucho family corepressors in peripheral T cells and demonstrate that specific mechanisms are activated in tolerant T helper cells to directly repress expression of effector cytokines, supporting the hypothesis that stable epigenetic imprinting contributes to the maintenance of the tolerance-associated hyporesponsive phenotype in T cells.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Sanmay
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Rut
authors.initials: R
authors.lastname: Valdor
authors.forename: Fernando
authors.initials: F
authors.lastname: Macian
mesh_terms: D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D017635:Clonal Anergy; D017124:Conserved Sequence; D015536:Down-Regulation; D063185:Epigenetic Repression; D005260:Female; D006657:Histones / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D006657:Histones; C513258:Prdm1 protein, mouse; D012097:Repressor Proteins; C434949:Tle4 protein, mouse; D014157:Transcription Factors; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1