title: Epigenetic changes at Il12rb2 and Tbx21 in relation to plasticity behavior of Th17 cells.
abstract: Plasticity within Th cell populations may play a role in enabling site-specific immune responses to infections while limiting tissue destruction. Epigenetic processes are fundamental to such plasticity; however, to date, most investigations have focused on in vitro-generated T cells. In this study, we have examined the molecular mechanisms underpinning murine Th17 plasticity in vivo by assessing H3K4 and H3K27 trimethylation marks at Tbx21, Rorc, Il17a, Ifng, and Il12rb2 loci in purified ex vivo-isolated and in vitro-generated Th17 cells. Although both populations had largely comparable epigenetic signatures, including bivalent marks at Tbx21, freshly isolated ex vivo Th17 cells displayed restricted expression from Il12rb2 due to the presence of repressive chromatin modifications. This receptor, however, could be upregulated on isolated ex vivo Th17 cells after in vitro activation or by in vivo immunization and was augmented by the presence of IFN-γ. Such activated cells could then be deviated toward a Th1-like profile. We show that IL-12 stimulation removes H3K27 trimethylation modifications at Tbx21/T-bet leading to enhanced T-bet expression with in vitro Th17 cells. Our study reveals important potential phenotypic differences between ex vivo- and in vitro-generated Th17 cells and provides mechanistic insight into Th17 cell plasticity.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Bending
authors.forename: Stephen
authors.initials: S
authors.lastname: Newland
authors.forename: Alena
authors.initials: A
authors.lastname: Krejcí
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Phillips
authors.forename: Sarah
authors.initials: S
authors.lastname: Bray
authors.forename: Anne
authors.initials: A
authors.lastname: Cooke
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000276:immunology; D019175:DNA Methylation / Q000235:genetics / Q000276:immunology; D044127:Epigenesis, Genetic / Q000276:immunology*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D053707:Receptors, Interleukin-12 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: C508443:Il12rb2 protein, mouse; D053707:Receptors, Interleukin-12; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007041:Hypoxanthine Phosphoribosyltransferase