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The Journal of Immunology, 2004, 173: 7120-7124.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: CD28-Mediated Transcriptional and Posttranscriptional Regulation of IL-2 Expression Are Controlled through Different Signaling Pathways1

Mariano Sanchez-Lockhart*, Elides Marin*, Beth Graf*, Ryo Abe{dagger}, Yohsuke Harada{dagger}, Caitlin E. Sedwick2,* and Jim Miller3,*

* David H. Smith Center for Vaccine Biology and Immunology, Aab Institute, and Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642; and {dagger} Division of Immunobiology, Tokyo University of Science, Chiba, Japan

Despite the clear functional importance of CD28 costimulation, the signaling pathways transduced through CD28 have remained controversial. PI3K was identified early as a candidate for CD28 signaling, but conflicting data during the past decade has left the role of PI3K unresolved. In this report, we have resolved this controversy. We show that mutation of the PI3K interaction site in the cytosolic tail of CD28 site disrupts the ability of CD28 to recruit protein kinase C-{theta} to the central supramolecular activation cluster (c-SMAC) region of the immunological synapse, promote NF-{kappa}B nuclear translocation, and enhance IL-2 gene transcription. In contrast, mutation of the PI3K interaction site had no effect on the ability of CD28 to enhance IL-2 mRNA stability. These results suggest that two distinct pathways mediate CD28-induced up-regulation of IL-2 expression, a PI3K-dependent pathway that may function through the immunological synapse to enhance IL-2 transcription and a PI3K-independent pathway that induces IL-2 mRNA stability.




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