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.
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-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 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.
Fukumoto
Risaku
R
Animal Models and Retroviral Vaccines Section, National Cancer Institute, NIH, Bethesda, MD 20892-5065, USA.
Dundr
Miroslav
M
Nicot
Christophe
C
Adams
Anthony
A
Valeri
Valerio W
VW
Samelson
Lawrence E
LE
Franchini
Genoveffa
G
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D017353:Gene Deletion; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry; D008565:Membrane Proteins / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors; D009856:Oncogene Proteins, Viral / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins
D048868:Adaptor Proteins, Signal Transducing; C110810:LAT protein, human; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009856:Oncogene Proteins, Viral; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C084305:p12I protein, Human T-lymphotropic virus 1; D051966:Phospholipase C gamma