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TCF-1 Inhibits IL-17 Gene Expression To Restrain Th17 Immunity in a Stage-Specific Manner.

T cell factor 1 (TCF-1) is expressed in both developing and mature T cells and has been shown to restrain mature T cell–mediated Th17 responses by inhibiting IL-17 expression. However, it is not clear when TCF-1 is required in vivo to restrain the magnitude of peripheral Th17 responses and what the... Full description

Journal Title: Journal of immunology (Baltimore Md. : 1950), May 15, 2018, Vol.200(10), pp.3397-3406
Main Author: Zhang, Jing
Other Authors: He, Zhiheng , Sen, Subha , Wang, Fei , Zhang, Qiang , Sun, Zuoming
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1550-6606 ; DOI: 1550-6606 ; DOI: 10.4049/jimmunol.1800193
Link: http://search.proquest.com/docview/2023728818/?pq-origsite=primo
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title: TCF-1 Inhibits IL-17 Gene Expression To Restrain Th17 Immunity in a Stage-Specific Manner.
format: Article
creator:
  • Zhang, Jing
  • He, Zhiheng
  • Sen, Subha
  • Wang, Fei
  • Zhang, Qiang
  • Sun, Zuoming
subjects:
  • Animals–Immunology
  • Cd4-Positive T-Lymphocytes–Immunology
  • Cd8-Positive T-Lymphocytes–Genetics
  • Cell Differentiation–Immunology
  • Encephalomyelitis, Autoimmune, Experimental–Genetics
  • Gene Expression–Immunology
  • Hepatocyte Nuclear Factor 1-Alpha–Genetics
  • Histone Deacetylases–Immunology
  • Immunity–Immunology
  • Interleukin-17–Genetics
  • Mice–Immunology
  • Promoter Regions, Genetic–Genetics
  • Th17 Cells–Immunology
  • Thymocytes–Genetics
  • Thymocytes–Immunology
  • Thymocytes–Genetics
  • Thymocytes–Immunology
  • Thymocytes–Immunology
  • Thymocytes–Immunology
  • Abridged
  • Hepatocyte Nuclear Factor 1-Alpha
  • Hnf1a Protein, Mouse
  • Il17a Protein, Mouse
  • Interleukin-17
  • Histone Deacetylases
ispartof: Journal of immunology (Baltimore, Md. : 1950), May 15, 2018, Vol.200(10), pp.3397-3406
description: T cell factor 1 (TCF-1) is expressed in both developing and mature T cells and has been shown to restrain mature T cell–mediated Th17 responses by inhibiting IL-17 expression. However, it is not clear when TCF-1 is required in vivo to restrain the magnitude of peripheral Th17 responses and what the molecular mechanisms responsible for TCF-1–regulated IL-17 gene expression are. In this study, we showed that conditional deletion of TCF-1 at the early but not later CD4+CD8+ double-positive stage in mice enhanced Th17 differentiation and aggravated experimental autoimmune encephalomyelitis, which correlates with abnormally high IL-17 expression. Expression of TCF-1 in TCF-1–deficient thymocytes but not TCF-1–deficient Th17 cells inhibited IL-17 expression. TCF-1 binds to IL-17 promoter regions, and deletion of two TCF-1 binding sites relieves TCF-1–mediated inhibition of IL-17 promoter activity. Lastly, wild-type TCF-1, but not a TCF-1 mutant that has no intrinsic histone deacetylase activity, was able to inhibit IL-17 expression in TCF-1 deficient mouse thymocytes. Thus, our study demonstrates the requirement of TCF-1 in vivo at stages earlier than double-positive cells to restrain peripheral Th17 immunity by directly binding and inhibiting IL-17 promoter in its intrinsic histone deacetylase–dependent manner.
language: eng
source:
identifier: E-ISSN: 1550-6606 ; DOI: 1550-6606 ; DOI: 10.4049/jimmunol.1800193
fulltext: fulltext
issn:
  • 15506606
  • 1550-6606
url: Link


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titleTCF-1 Inhibits IL-17 Gene Expression To Restrain Th17 Immunity in a Stage-Specific Manner.
creatorZhang, Jing ; He, Zhiheng ; Sen, Subha ; Wang, Fei ; Zhang, Qiang ; Sun, Zuoming
contributorZhang, Jing (correspondence author) ; Zhang, Jing (record owner)
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subjectAnimals–Immunology ; Cd4-Positive T-Lymphocytes–Immunology ; Cd8-Positive T-Lymphocytes–Genetics ; Cell Differentiation–Immunology ; Encephalomyelitis, Autoimmune, Experimental–Genetics ; Gene Expression–Immunology ; Hepatocyte Nuclear Factor 1-Alpha–Genetics ; Histone Deacetylases–Immunology ; Immunity–Immunology ; Interleukin-17–Genetics ; Mice–Immunology ; Promoter Regions, Genetic–Genetics ; Th17 Cells–Immunology ; Thymocytes–Genetics ; Thymocytes–Immunology ; Thymocytes–Genetics ; Thymocytes–Immunology ; Thymocytes–Immunology ; Thymocytes–Immunology ; Abridged ; Hepatocyte Nuclear Factor 1-Alpha ; Hnf1a Protein, Mouse ; Il17a Protein, Mouse ; Interleukin-17 ; Histone Deacetylases
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descriptionT cell factor 1 (TCF-1) is expressed in both developing and mature T cells and has been shown to restrain mature T cell–mediated Th17 responses by inhibiting IL-17 expression. However, it is not clear when TCF-1 is required in vivo to restrain the magnitude of peripheral Th17 responses and what the molecular mechanisms responsible for TCF-1–regulated IL-17 gene expression are. In this study, we showed that conditional deletion of TCF-1 at the early but not later CD4+CD8+ double-positive stage in mice enhanced Th17 differentiation and aggravated experimental autoimmune encephalomyelitis, which correlates with abnormally high IL-17 expression. Expression of TCF-1 in TCF-1–deficient thymocytes but not TCF-1–deficient Th17 cells inhibited IL-17 expression. TCF-1 binds to IL-17 promoter regions, and deletion of two TCF-1 binding sites relieves TCF-1–mediated inhibition of IL-17 promoter activity. Lastly, wild-type TCF-1, but not a TCF-1 mutant that has no intrinsic histone deacetylase activity, was able to inhibit IL-17 expression in TCF-1 deficient mouse thymocytes. Thus, our study demonstrates the requirement of TCF-1 in vivo at stages earlier than double-positive cells to restrain peripheral Th17 immunity by directly binding and inhibiting IL-17 promoter in its intrinsic histone deacetylase–dependent manner.
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