The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published online 10 April 2006 doi:10.1084/jem.20052333
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 4, 1021-1031
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ARTICLE

 Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor–ß1

Ichiko Kinjyo1, Hiromasa Inoue2, Shinjiro Hamano3, Satoru Fukuyama1,2, Takeru Yoshimura1, Keiko Koga1, Hiromi Takaki1, Kunisuke Himeno3, Giichi Takaesu1, Takashi Kobayashi1, and Akihiko Yoshimura1

1 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, 2 Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, and 3 Department of Parasitology, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan

CORRESPONDENCE Akihiko Yoshimura: yakihiko{at}bioreg.kyushu-u.ac.jp

Suppressor of cytokine signaling (SOCS)3 is a major negative feedback regulator of signal transducer and activator of transcription (STAT)3-activating cytokines. Transgenic mouse studies indicate that high levels of SOCS3 in T cells result in type 2 T helper cell (Th2) skewing and lead to hypersensitivity to allergic diseases. To define the physiological roles of SOCS3 in T cells, we generated T cell–specific SOCS3 conditional knockout mice. We found that the mice lacking SOCS3 in T cells showed reduced immune responses not only to ovalbumin-induced airway hyperresponsiveness but also to Leishmania major infection. In vitro, SOCS3-deficient CD4+ T cells produced more transforming growth factor (TGF)-ß1 and interleukin (IL)-10, but less IL-4 than control T cells, suggesting preferential Th3-like differentiation. We found that STAT3 positively regulates TGF-ß1 promoter activity depending on the potential STAT3 binding sites. Furthermore, chromatin immunoprecipitation assay revealed that more STAT3 was recruited to the TGF-ß1 promoter in SOCS3-deficient T cells than in control T cells. The activated STAT3 enhanced TGF-ß1 and IL-10 expression in T cells, whereas the dominant-negative form of STAT3 suppressed these. From these findings, we propose that SOCS3 regulates the production of the immunoregulatory cytokines TGF-ß1 and IL-10 through modulating STAT3 activation.

Abbreviations used: ChIP, chromatin immunoprecipitation; cKO, conditional KO; LIF, leukemia inhibitory factor; SH2, Src homology 2; SBE, STAT3-binding element; SOCS, suppressor of cytokine signaling.


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