The Journal of Experimental Medicine
StemCell Technologies
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Published online 10 February 2003 doi:10.1084/jem.20020939
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© Rockefeller University Press, 0022-1007/2003/2/425 $5.00
The Journal of Experimental Medicine, Volume 197, Number 4, 425-436

A Role of Suppressor of Cytokine Signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated Interleukin 2 Production

Akira Matsumoto1,3, Yoh-ichi Seki1, Ryosuke Watanabe1, Katsuhiko Hayashi2, James A. Johnston4, Yohsuke Harada1, Ryo Abe1, Akihiko Yoshimura3 and Masato Kubo1

1 Research Institute for Biological Sciences, Tokyo University of Science, Chiba 278-0022, Japan
2 Division of Molecularbiology, Tokyo University of Science, Chiba 278-0022, Japan
3 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Higashi-hu Fukuoka 812-8582, Japan
4 Department of Immunology, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland

Address correspondence to Masato Kubo, Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda City, Chiba 278-0022, Japan. Phone: 81-471-23-9770; Fax: 81-471-25-2887; E-mail: raysolfc{at}rs.noda.sut.ac.jp

Suppressor of cytokine signaling (SOCS)3 has been characterized as a negative feedback regulator in cytokine-mediated Janus kinase signal transducer and activator of transcription signaling. However, this study shows that T cells from transgenic mice expressing SOCS3 exhibit a significant reduction in interleukin (IL)-2 production induced by T cell receptor cross-linking when T cells are costimulated with CD28. Decreased protein expression in SOCS3+/- mice enhanced CD28-mediated IL-2 production, clearly indicating the correlation between expression level of SOCS3 and IL-2 production ability. The SOCS3 protein interacted with phosphorylated CD28 through its SH2 domain but not the kinase inhibitory region. In addition, a point mutation in the SOCS3 SH2 domain attenuated the inhibition of CD28 function in IL-2 promoter activation. Committed T helper (Th)2 cells exclusively expressed SOCS3 and production of Th2 cytokines, such as IL-4 and IL-5, was much less dependent on CD28 costimulation compared with interferon {gamma} and IL-2 production in Th1 cells. Consistent with this notion, the expression level of SOCS3 in early T cell activation influenced the ability of IL-2 production induced by CD28 costimulation. Therefore, the SOCS3 may play an alternative role in prohibiting excessive progression of CD28-mediated IL-2 production.

Key Words: CD28 • costimulation • IL-2 production • SOCS • T cell activation


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