The Journal of Experimental Medicine
Cytokines in immune regulation
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Published 20 January 2003. doi:10.1084/jem.20021305
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© Rockefeller University Press, 0022-1007/2003/1/257 $5.00
The Journal of Experimental Medicine, Volume 197, Number 2, 257-262

Brief Definitive Report

 A Single Amino Acid Alteration in Cytoplasmic Domain Determines IL-2 Promoter Activation by Ligation of CD28 but Not Inducible Costimulator (ICOS)

Yohsuke Harada1, Daisuke Ohgai1, Ryosuke Watanabe1, Kazuhiro Okano1, Osamu Koiwai3, Kazunari Tanabe4, Hiroshi Toma4, Amnon Altman5 and Ryo Abe1,2

1 Research Institute for Biological Sciences, Faculty of Science and Technology, Tokyo University of Science, Chiba 278-0022, Japan
2 Genome and Drug Research Center, Faculty of Science and Technology, Tokyo University of Science, Chiba 278-0022, Japan
3 Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba 278-0022, Japan
4 Department of Urology, Tokyo Women's Medical University, Tokyo 162-8666, Japan
5 Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

Address correspondence to Dr. Ryo Abe, Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan. Phone: 81-4-7123-9756; Fax: 81-4-7124-1955; E-mail: rabe{at}rs.noda.tus.ac.jp

The CD28 family molecules, CD28, and inducible costimulator (ICOS) all provide positive costimulatory signals. However, unlike CD28, ICOS does not costimulate IL-2 secretion. The YMNM motif that exists in the CD28 cytoplasmic domain is a known binding site for phosphatidylinositol 3-kinase (PI3-K) and Grb2. ICOS possesses the YMFM motif in the corresponding region of CD28 that binds PI3-K but not Grb2. We postulated that the reason that ICOS does not have the ability to induce IL-2 production is because it fails to recruit Grb2. To verify this hypothesis, we generated a mutant ICOS gene that contains the CD28 YMNM motif and measured IL-2 promoter activation after ICOS ligation. The results indicated that ICOS became competent to activate the IL-2 promoter by this single alteration. Further analysis demonstrated that Grb2 binding to ICOS was sufficient to activate the NFAT/AP-1 site in the IL-2 promoter and that the cytoplasmic domain of CD28 outside of the YMNM motif is required for activation of the CD28RE/AP-1 and NF-{kappa}B sites. Together, these observations lead us to believe that the difference of a single amino acid, which affects Grb2 binding ability, may define a functional difference between the CD28- and ICOS-mediated costimulatory signals.

Key Words: Grb2 • Phosphatidylinositol 3-kinase • NFAT • AP-1 • NF-{kappa}b


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