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

Author:

Fukumoto Risaku1,Dundr Miroslav1,Nicot Christophe1,Adams Anthony2,Valeri Valerio W.1,Samelson Lawrence E.3,Franchini Genoveffa1

Affiliation:

1. Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland 20892-5065

2. Experimental Immunology Branch, National Cancer Institute, 10/4B36, Bethesda, Maryland 20892

3. Laboratory of Cellular and Molecular Biology, National Cancer Institute, 37/1E24, Bethesda, Maryland 20892

Abstract

ABSTRACT 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-γ1 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.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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