title: Critical role of TCF-1 in repression of the IL-17 gene.
abstract: Overwhelming activation of IL-17, a gene involved in inflammation, leads to exaggerated Th17 responses associated with numerous autoimmune conditions, such as experimental autoimmune encephalomyelitis (EAE). Here we show that TCF-1 is a critical factor to repress IL-17 gene locus by chromatin modifications during T cell development. Deletion of TCF-1 resulted in increased IL-17 gene expression both in thymus and peripheral T cells, which led to enhanced Th17 differentiation. As a result, TCF-1(-/-) mice were susceptible to Th17-dependent EAE induction. Rag1(-/-) mice reconstituted with TCF-1(-/-) T cells were also susceptible to EAE, indicating TCF-1 is intrinsically required to repress IL-17. However, expression of wild-type TCF-1 or dominant negative TCF-1 did not interfere with Th17 differentiation in mature T cells. Furthermore, expression of TCF-1 in TCF-1(-/-) T cells could not restore Th17 differentiation to wild-type levels, indicating that TCF-1 cannot affect IL-17 production at the mature T cell stage. This is also supported by the normal up-regulation or activation in mature TCF-1(-/-) T cells of factors known to regulate Th17 differentiation, including RORγt and Stat3. We observed hyperacetylation together with trimethylation of Lys-4 at the IL-17 locus in TCF-1(-/-) thymocytes, two epigenetic modifications indicating an open active state of the gene. Such epigenetic modifications were preserved even when TCF-1(-/-) T cells migrated out of thymus. Therefore, TCF-1 mediates an active process to repress IL-17 gene expression via epigenetic modifications during T cell development. This TCF-1-mediated repression of IL-17 is critical for peripheral T cells to generate balanced immune responses.
authors.affiliation: Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.forename: Ruiqing
authors.initials: R
authors.lastname: Wang
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Fang
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051822:T Cell Transcription Factor 1