Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-γ on STAT3 and Smads

Kentaro Tanaka, Kenji Ichiyama, Masayuki Hashimoto, Hideyuki Yoshida, Tomohito Takimoto, Giichi Takaesu, Takehiro Torisu, Toshikatsu Hanada, Hideo Yasukawa, Satoru Fukuyama, Hiromasa Inoue, Yoichi Nakanishi, Takashi Kobayashi, Akihiko Yoshimura

Research output: Contribution to journalArticle

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Abstract

Suppressor of cytokine signaling 1 (SOCS1) is an important negative regulator for cytokines; however, the role of SOCS1 in Th17 differentiation has not been clarified. We generated T cell-specific SOCS1-deficient mice and found that these mice were extremely resistant to a Th17-dependent autoimmune disease model, experimental autoimmune encephalomyelitis. SOCS1-deficient naive CD4 + T cells were predominantly differentiated into Th1 and poorly into Th17 in vitro. These phenotypes were canceled in IFN-γ-/- background, suggesting that a large amount of IFN-γ in SOCS1-deficient T cells suppressed Th17 differentiation. IL-6 plus TGF-β enhanced retinoic acid receptor-related orphan receptor (ROR)-γt expression and suppressed IFN-γ production in wild-type T cells, whereas these effects were severely impaired in SOCS1-deficient T cells. These phenotypes can be partly explained by STAT3 suppression by enhanced SOCS3 induction through hyper-STAT1 activation in SOCS1-deficient T cells. In addition, SOCS1-deficient T cells were much less sensitive to TGF-β. Suppression of Th1 differentiation by TGF-β was impaired in SOCS1-deficient T cells. TGF-β-mediated Smad transcriptional activity was severely inhibited in SOCS1-deficient cells in the presence of IFN-γ. Such impairment of TGF-γ functions were not observed in SOCS3-overexpressed cells, indicating that suppression of Smads was independent of SOCS3. Therefore, SOCS1 is necessary for Th17 differentiation by suppressing antagonistic effect of IFN-γ on both STAT3 and Smads. Induction of SOCS3 can partly explain IFN-γ-mediated STAT3 suppression, while other mechanism(s) will be involved in IFN-β-mediated Smad suppression. SOCS1-deficient T cells will be very useful to investigate the molecular mechanism for the STAT1-mediated suppression of Th17 development.

Original languageEnglish
Pages (from-to)3746-3756
Number of pages11
JournalJournal of Immunology
Volume180
Issue number6
Publication statusPublished - 2008 Mar 15
Externally publishedYes

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Th1 Cells
Cytokines
T-Lymphocytes
Phenotype
Retinoic Acid Receptors
Autoimmune Experimental Encephalomyelitis
Autoimmune Diseases
Interleukin-6

ASJC Scopus subject areas

  • Immunology

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Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-γ on STAT3 and Smads. / Tanaka, Kentaro; Ichiyama, Kenji; Hashimoto, Masayuki; Yoshida, Hideyuki; Takimoto, Tomohito; Takaesu, Giichi; Torisu, Takehiro; Hanada, Toshikatsu; Yasukawa, Hideo; Fukuyama, Satoru; Inoue, Hiromasa; Nakanishi, Yoichi; Kobayashi, Takashi; Yoshimura, Akihiko.

In: Journal of Immunology, Vol. 180, No. 6, 15.03.2008, p. 3746-3756.

Research output: Contribution to journalArticle

Tanaka, K, Ichiyama, K, Hashimoto, M, Yoshida, H, Takimoto, T, Takaesu, G, Torisu, T, Hanada, T, Yasukawa, H, Fukuyama, S, Inoue, H, Nakanishi, Y, Kobayashi, T & Yoshimura, A 2008, 'Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-γ on STAT3 and Smads', Journal of Immunology, vol. 180, no. 6, pp. 3746-3756.
Tanaka, Kentaro ; Ichiyama, Kenji ; Hashimoto, Masayuki ; Yoshida, Hideyuki ; Takimoto, Tomohito ; Takaesu, Giichi ; Torisu, Takehiro ; Hanada, Toshikatsu ; Yasukawa, Hideo ; Fukuyama, Satoru ; Inoue, Hiromasa ; Nakanishi, Yoichi ; Kobayashi, Takashi ; Yoshimura, Akihiko. / Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-γ on STAT3 and Smads. In: Journal of Immunology. 2008 ; Vol. 180, No. 6. pp. 3746-3756.
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AU - Tanaka, Kentaro

AU - Ichiyama, Kenji

AU - Hashimoto, Masayuki

AU - Yoshida, Hideyuki

AU - Takimoto, Tomohito

AU - Takaesu, Giichi

AU - Torisu, Takehiro

AU - Hanada, Toshikatsu

AU - Yasukawa, Hideo

AU - Fukuyama, Satoru

AU - Inoue, Hiromasa

AU - Nakanishi, Yoichi

AU - Kobayashi, Takashi

AU - Yoshimura, Akihiko

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