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Molecular and Cellular Biology, November 2005, p. 9543-9553, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9543-9553.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms{dagger}

Richard V. Parry,1,2,{ddagger} Jens M. Chemnitz,1,2,{ddagger} Kenneth A. Frauwirth,1,3 Anthony R. Lanfranco,1,2 Inbal Braunstein,1,2 Sumire V. Kobayashi,4 Peter S. Linsley,4 Craig B. Thompson,1,3 and James L. Riley1,2*

Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1 Department of Pathology and Laboratory Medicine,2 Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160,3 Rosetta Inpharmatics, Kirkland, Washington 980344

Received 14 March 2005/ Returned for modification 14 April 2005/ Accepted 18 August 2005

CTLA-4 and PD-1 are receptors that negatively regulate T-cell activation. Ligation of both CTLA-4 and PD-1 blocked CD3/CD28-mediated upregulation of glucose metabolism and Akt activity, but each accomplished this regulation using separate mechanisms. CTLA-4-mediated inhibition of Akt phosphorylation is sensitive to okadaic acid, providing direct evidence that PP2A plays a prominent role in mediating CTLA-4 suppression of T-cell activation. In contrast, PD-1 signaling inhibits Akt phosphorylation by preventing CD28-mediated activation of phosphatidylinositol 3-kinase (PI3K). The ability of PD-1 to suppress PI3K/AKT activation was dependent upon the immunoreceptor tyrosine-based switch motif located in its cytoplasmic tail, adding further importance to this domain in mediating PD-1 signal transduction. Lastly, PD-1 ligation is more effective in suppressing CD3/CD28-induced changes in the T-cell transcriptional profile, suggesting that differential regulation of PI3K activation by PD-1 and CTLA-4 ligation results in distinct cellular phenotypes. Together, these data suggest that CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms.

* Corresponding author. Mailing address: Abramson Family Cancer Research Institute, 556 BRB II/III, 421 Curie Blvd., University of Pennsylvania, Philadelphia, PA 19104. Phone: (215) 573-6792. Fax: (215) 573-8590. E-mail: rileyj{at}mail.med.upenn.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, November 2005, p. 9543-9553, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9543-9553.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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