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J Exp Med. 2014 Aug 25;211(9):1857-74. doi: 10.1084/jem.20130791. Epub 2014 Jul 29.

Sox5 and c-Maf cooperatively induce Th17 cell differentiation via RORγt induction as downstream targets of Stat3.

Author information

1
Department of Allergy and Clinical Immunology and Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
2
Department of Allergy and Clinical Immunology and Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan suaki@faculty.chiba-u.jp nakajimh@faculty.chiba-u.jp.
3
Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
4
Department of Allergy and Clinical Immunology and Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan Department of Immunology and Host Defenses, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan.
5
Department of Allergy and Clinical Immunology and Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan Core Research for Evolutional Science and Technology (CREST), Japan science and Technology Agency, Tokyo 102-0076, Japan.

Abstract

Stat3 signaling is essential for the induction of RORγt and subsequent Th17 cell differentiation. However, the downstream targets of Stat3 for RORγt expression remain largely unknown. We show here that a novel isoform of Sox5, named Sox5t, is induced in Th17 cells in a Stat3-dependent manner. In vivo, T cell-specific Sox5-deficient mice exhibit impaired Th17 cell differentiation and are resistant to experimental autoimmune encephalomyelitis and delayed-type hypersensitivity. Retrovirus-mediated induction of Sox5 together with c-Maf induces Th17 cell differentiation even in Stat3-deficient CD4(+) T cells but not in RORγt-deficient CD4(+) T cells, indicating that Sox5 and c-Maf induce Th17 cell differentiation as downstream effectors of Stat3 and as upstream inducers of RORγt. Moreover, Sox5 physically associates with c-Maf via the HMG domain of Sox5 and DNA-binding domain of c-Maf, and Sox5 together with c-Maf directly activates the promoter of RORγt in CD4(+) T cells. Collectively, our results suggest that Sox5 and c-Maf cooperatively induce Th17 cell differentiation via the induction of RORγt as downstream targets of Stat3.

PMID:
25073789
PMCID:
PMC4144730
DOI:
10.1084/jem.20130791
[Indexed for MEDLINE]
Free PMC Article
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