The Journal of Experimental Medicine
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Published online 20 March 2000.
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© The Rockefeller University Press, 0022-1007/2000/3/985/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 6, March 20, 2000 985-994

Original Article

Cytokine-Induced Src Homology 2 Protein (Cis) Promotes T Cell Receptor–Mediated Proliferation and Prolongs Survival of Activated T Cells

Suling Lia, Shangwu Chena, Xiufeng Xub, Anette Sundstedta, Kajsa M. Paulssona, Per Andersona, Stefan Karlssonb, Hans-Olov Sjögrena, and Ping Wanga

a Department of Tumor Immunology, Lund University, S-22362 Lund, Sweden
b Department of Molecular Medicine and Gene Therapy, Lund University, S-22362 Lund, Sweden
Tumor Immunology, Lund University, Slovegatan 21, S-22362 Lund, Sweden.46-46-222460646-46-2227848

su-ling.li{at}wblab.lu.se

ping.wang{at}wblab.lu.se

Members of the suppressor of cytokine signaling (SOCS) family were discovered as negative regulators of cytokine signaling by inhibition of the Janus kinase–signal transducer and activator of transcription (Jak-STAT) pathway. Among them, cytokine-induced Src homology 2 (SH2) protein (CIS) was found to inhibit the interleukin 3– and erythropietin-mediated STAT5 signaling pathway. However, involvement of SOCS proteins in other signaling pathways is still unknown. This study shows that the expression of CIS is selectively induced in T cells after T cell receptor (TCR) stimulation. In transgenic mice, with selective expression of CIS in CD4 T cells, elevated CIS strongly promotes TCR-mediated proliferation and cytokine production in vitro, and superantigen-induced T cell activation in vivo. Forced expression of CIS also prolongs survival of CD4 T cells after TCR activation. Molecular events immediately downstream from the TCR are not changed in CIS-expressing CD4 T cells, but activation of mitogen-activated protein (MAP) kinase pathways by TCR stimulation is significantly enhanced. Together with the increased MAP kinase activation, a direct interaction of CIS and protein kinase C{theta} was also demonstrated. These results suggest that CIS is one of the important regulators of TCR-mediated T cell activation. The functions of CIS, enhancing TCR signaling and inhibiting cytokine signaling, may be important in the regulation of immune response and homeostasis.

Key Words: cytokine-induced SH2 protein • T cell receptor • signal transduction • mitogen-activated protein kinases • T cell activation

Abbreviations used in this paper: AP-1, activating protein 1; ATF, activating transcription factor; CIS, cytokine-induced SH2 protein(s); ERK, extracellular signal–regulated kinase; G3PDH, glyceraldehyde 3-phosphate dehydrogenase; GST, glutathione S-transferase; JNK, c-Jun NH2-terminal kinase; LAT, linker for activation of T cells; MAP, mitogen-activated protein; MBP, myelin basic protein; PKC, protein kinase C; SEA, staphylococcal enterotoxin A; SH2, Src homology 2; SLP-76, SH2 domain–containing leukocyte protein of 76 kD; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription.

© 2000 The Rockefeller University Press


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