Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-gamma on STAT3 and Smads.
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-gamma(-/-) background, suggesting that a large amount of IFN-gamma in SOCS1-deficient T cells suppressed Th17 differentiation. IL-6 plus TGF-beta enhanced retinoic acid receptor-related orphan receptor (ROR)-gammat expression and suppressed IFN-gamma 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-beta. Suppression of Th1 differentiation by TGF-beta was impaired in SOCS1-deficient T cells. TGF-beta-mediated Smad transcriptional activity was severely inhibited in SOCS1-deficient cells in the presence of IFN-gamma. Such impairment of TGF-beta 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-gamma on both STAT3 and Smads. Induction of SOCS3 can partly explain IFN-gamma-mediated STAT3 suppression, while other mechanism(s) will be involved in IFN-gamma-mediated Smad suppression. SOCS1-deficient T cells will be very useful to investigate the molecular mechanism for the STAT1-mediated suppression of Th17 development.
Tanaka
Kentaro
K
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Ichiyama
Kenji
K
Hashimoto
Masayuki
M
Yoshida
Hideyuki
H
Takimoto
Tomohito
T
Takaesu
Giichi
G
Torisu
Takehiro
T
Hanada
Toshikatsu
T
Yasukawa
Hideo
H
Fukuyama
Satoru
S
Inoue
Hiromasa
H
Nakanishi
Yoichi
Y
Kobayashi
Takashi
T
Yoshimura
Akihiko
A
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D020381:Interleukin-17 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051785:Smad Proteins / Q000037:antagonists & inhibitors*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D020381:Interleukin-17; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D051785:Smad Proteins; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma