This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Parry, R. V.
Right arrow Articles by Riley, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Parry, R. V.
Right arrow Articles by Riley, J. L.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Hsieh, C.-H., Hsu, J.-T., Hsieh, Y.-C., Frink, M., Raju, R., Hubbard, W. J., Bland, K. I., Chaudry, I. H. (2009). Suppression of Activation and Costimulatory Signaling in Splenic CD4+ T Cells after Trauma-Hemorrhage Reduces T-Cell Function: A Mechanism of Post-Traumatic Immune Suppression. Am. J. Pathol. 175: 1504-1514 [Abstract] [Full Text]  
  • Nagamatsu, T., Schust, D. J., Sugimoto, J., Barrier, B. F. (2009). Human decidual stromal cells suppress cytokine secretion by allogenic CD4+ T cells via PD-1 ligand interactions. Hum Reprod 0: dep308v1-dep308 [Abstract] [Full Text]  
  • Ahmadzadeh, M., Johnson, L. A., Heemskerk, B., Wunderlich, J. R., Dudley, M. E., White, D. E., Rosenberg, S. A. (2009). Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114: 1537-1544 [Abstract] [Full Text]  
  • Petrovas, C., Chaon, B., Ambrozak, D. R., Price, D. A., Melenhorst, J. J., Hill, B. J., Geldmacher, C., Casazza, J. P., Chattopadhyay, P. K., Roederer, M., Douek, D. C., Mueller, Y. M., Jacobson, J. M., Kulkarni, V., Felber, B. K., Pavlakis, G. N., Katsikis, P. D., Koup, R. A. (2009). Differential Association of Programmed Death-1 and CD57 with Ex Vivo Survival of CD8+ T Cells in HIV Infection. J. Immunol. 183: 1120-1132 [Abstract] [Full Text]  
  • Kaufmann, D. E., Walker, B. D. (2009). PD-1 and CTLA-4 Inhibitory Cosignaling Pathways in HIV Infection and the Potential for Therapeutic Intervention. J. Immunol. 182: 5891-5897 [Abstract] [Full Text]  
  • Finnefrock, A. C., Tang, A., Li, F., Freed, D. C., Feng, M., Cox, K. S., Sykes, K. J., Guare, J. P., Miller, M. D., Olsen, D. B., Hazuda, D. J., Shiver, J. W., Casimiro, D. R., Fu, T.-M. (2009). PD-1 Blockade in Rhesus Macaques: Impact on Chronic Infection and Prophylactic Vaccination. J. Immunol. 182: 980-987 [Abstract] [Full Text]  
  • Flores-Borja, F., Jury, E. C., Mauri, C., Ehrenstein, M. R. (2008). Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 105: 19396-19401 [Abstract] [Full Text]  
  • Estes, J. D., Gordon, S. N., Zeng, M., Chahroudi, A. M., Dunham, R. M., Staprans, S. I., Reilly, C. S., Silvestri, G., Haase, A. T. (2008). Early Resolution of Acute Immune Activation and Induction of PD-1 in SIV-Infected Sooty Mangabeys Distinguishes Nonpathogenic from Pathogenic Infection in Rhesus Macaques. J. Immunol. 180: 6798-6807 [Abstract] [Full Text]  
  • Edgtton, K. L., Kausman, J. Y., Li, M., O'Sullivan, K., Lo, C., Hutchinson, P., Yagita, H., Holdsworth, S. R., Kitching, A. R. (2008). Intrarenal Antigens Activate CD4+ Cells via Co-stimulatory Signals from Dendritic Cells. J. Am. Soc. Nephrol. 19: 515-526 [Abstract] [Full Text]  
  • Palmer, B. E., Mack, D. G., Martin, A. K., Gillespie, M., Mroz, M. M., Maier, L. A., Fontenot, A. P. (2008). Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease. J. Immunol. 180: 2704-2712 [Abstract] [Full Text]  
  • Wong, R. M., Scotland, R. R., Lau, R. L., Wang, C., Korman, A. J., Kast, W. M., Weber, J. S. (2007). Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int Immunol 19: 1223-1234 [Abstract] [Full Text]  
  • D'Souza, M., Fontenot, A. P., Mack, D. G., Lozupone, C., Dillon, S., Meditz, A., Wilson, C. C., Connick, E., Palmer, B. E. (2007). Programmed Death 1 Expression on HIV-Specific CD4+ T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction. J. Immunol. 179: 1979-1987 [Abstract] [Full Text]  
  • Okazaki, T., Honjo, T. (2007). PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 0: dxm057v1- [Abstract] [Full Text]  
  • Velu, V., Kannanganat, S., Ibegbu, C., Chennareddi, L., Villinger, F., Freeman, G. J., Ahmed, R., Amara, R. R. (2007). Elevated Expression Levels of Inhibitory Receptor Programmed Death 1 on Simian Immunodeficiency Virus-Specific CD8 T Cells during Chronic Infection but Not after Vaccination. J. Virol. 81: 5819-5828 [Abstract] [Full Text]  
  • Maier, H., Isogawa, M., Freeman, G. J., Chisari, F. V. (2007). PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver. J. Immunol. 178: 2714-2720 [Abstract] [Full Text]  
  • Petrovas, C., Casazza, J. P., Brenchley, J. M., Price, D. A., Gostick, E., Adams, W. C., Precopio, M. L., Schacker, T., Roederer, M., Douek, D. C., Koup, R. A. (2006). PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. JEM 203: 2281-2292 [Abstract] [Full Text]  
  • Freeman, G. J., Wherry, E. J., Ahmed, R., Sharpe, A. H. (2006). Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. JEM 203: 2223-2227 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»