title: Ikaros sets the potential for Th17 lineage gene expression through effects on chromatin state in early T cell development.
abstract: Th17 cells are important effectors of immunity to extracellular pathogens, particularly at mucosal surfaces, but they can also contribute to pathologic tissue inflammation and autoimmunity. Defining the multitude of factors that influence their development is therefore of paramount importance. Our previous studies using Ikaros(-/-) CD4+ T cells implicated Ikaros in Th1 versus Th2 lineage decisions. Here we demonstrate that Ikaros also regulates Th17 differentiation through its ability to promote expression of multiple Th17 lineage-determining genes, including Ahr, Runx1, Rorc, Il17a, and Il22. Ikaros exerts its influence on the chromatin remodeling of these loci at two distinct stages in CD4+ T helper cell development. In naive cells, Ikaros is required to limit repressive chromatin modifications at these gene loci, thus maintaining the potential for expression of the Th17 gene program. Subsequently, Ikaros is essential for the acquisition of permissive histone marks in response to Th17 polarizing signals. Additionally, Ikaros represses the expression of genes that limit Th17 development, including Foxp3 and Tbx21. These data define new targets of the action of Ikaros and indicate that Ikaros plays a critical role in CD4+ T cell differentiation by integrating specific cytokine cues and directing epigenetic modifications that facilitate activation or repression of relevant genes that drive T cell lineage choice.
authors.affiliation: From the Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Larry Y
authors.initials: LY
authors.lastname: Wong
authors.forename: Julianne K
authors.initials: JK
authors.lastname: Hatfield
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Brown
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016923:Cell Death; D019070:Cell Lineage; D042002:Chromatin Assembly and Disassembly; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis; D006657:Histones / Q000378:metabolism; D051740:Ikaros Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones; D020381:Interleukin-17; D018336:Receptors, Aryl Hydrocarbon; C493726:Runx1 protein, mouse; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor
keywords: Gene Regulation; Immunology; T Cell; Transcription Factors; Transcription Regulation