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Journal of Virology, September 2007, p. 9088-9099, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.02703-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1{triangledown}

Risaku Fukumoto,1 Miroslav Dundr,1,{dagger} Christophe Nicot,1,{ddagger} Anthony Adams,2 Valerio W. Valeri,1 Lawrence E. Samelson,3 and Genoveffa Franchini1*

Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland 20892-5065,1 Experimental Immunology Branch, National Cancer Institute, 10/4B36, Bethesda, Maryland 20892,2 Laboratory of Cellular and Molecular Biology, National Cancer Institute, 37/1E24, Bethesda, Maryland 208923

Received 7 December 2006/ Accepted 8 June 2007

The p12I protein of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is a small oncoprotein that increases calcium release following protein kinase C activation by phorbol myristate acetate, and importantly, this effect is linker for activation of T cells (LAT) independent. Here, we demonstrate that p12I inhibits the phosphorylation of LAT, Vav, and phospholipase C-{gamma}1 and decreases NFAT (nuclear factor of activated T cells) activation upon engagement of the T-cell receptor (TCR) with anti-CD3 antibody. Furthermore, we demonstrate that p12I localizes to membrane lipid rafts and, upon engagement of the TCR, relocalizes to the interface between T cells and antigen-presenting cells, defined as the immunological synapse. A p12I knockout molecular clone of HTLV-1 expresses more virus upon antigen stimulation than the isogenic wild type, suggesting that, by decreasing T-cell responsiveness, p12I curtails viral expression. Thus, p12I has contrasting effects on TCR signaling: it down-regulates TCR in a LAT-dependent manner on one hand, and on the other, it increases calcium release in a LAT-independent manner. The negative regulation of T-cell activation by p12I may have evolved to minimize immune recognition of infected CD4+ T cells, to impair the function of infected cytotoxic CD8+ T cells, and to favor viral persistence in the infected host.

* Corresponding author. Mailing address: Basic Research Laboratory, National Cancer Institute, NIH, Bldg. 41, Rm. D804, Bethesda, MD 20892-5065. Phone: (301) 496-2386. Fax: (301) 402-0055. E-mail: franchig{at}mail.nih.gov

{triangledown} Published ahead of print on 20 June 2007.

{dagger} Present address: Department of Cell Biology and Anatomy, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064.

{ddagger} Present address: Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, 3025 Wahl Hall West, 3901 Rainbow Boulevard, Kansas City, KS 66160.

Journal of Virology, September 2007, p. 9088-9099, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.02703-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Fukumoto, R., Andresen, V., Bialuk, I., Cecchinato, V., Walser, J.-C., Valeri, V. W., Nauroth, J. M., Gessain, A., Nicot, C., Franchini, G. (2009). In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein. Blood 113: 3726-3734 [Abstract] [Full Text]  
  • Jerome, K. R. (2008). Viral Modulation of T-Cell Receptor Signaling. J. Virol. 82: 4194-4204 [Full Text]  
  • Taylor, G P (2007). Molecular aspects of HTLV-I infection and adult T-cell leukaemia/lymphoma. J. Clin. Pathol. 60: 1392-1396 [Abstract] [Full Text]  


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