This Article Full Text Full Text (PDF) Other Versions of this Article: JVI.02703-06v1 81/17/9088    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fukumoto, R. Articles by Franchini, G. Search for Related Content PubMed PubMed Citation Articles by Fukumoto, R. Articles by Franchini, G.

 Previous Article  |  Next Article 

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 p12^I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Risaku Fukumoto,¹ Miroslav Dundr,^1, Christophe Nicot,^1, Anthony Adams,² Valerio W. Valeri,¹ Lawrence E. Samelson,³ and Genoveffa Franchini^1*

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 p12^I 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 p12^I inhibits the phosphorylation of LAT, Vav, and phospholipase C-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 p12^I 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 p12^I knockout molecular clone of HTLV-1 expresses more virus upon antigen stimulation than the isogenic wild type, suggesting that, by decreasing T-cell responsiveness, p12^I curtails viral expression. Thus, p12^I 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 p12^I 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.

Published ahead of print on 20 June 2007.

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

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.

This article has been cited by other articles:

• 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]