HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-alpha.
Plasmacytoid dendritic cells (pDC) are key players in viral immunity and produce IFN-alpha after HIV-1 exposure, which in turn regulates TNF-related apoptosis-inducing ligand (TRAIL) expression by CD4(+) T cells. We show here that infectious and noninfectious HIV-1 virions induce activation of pDC into TRAIL-expressing IFN-producing killer pDC (IKpDC). IKpDC expressed high levels of activation markers (HLA-DR, CD80, CD83, and CD86) and the migration marker CCR7. Surprisingly, CXCR4 and CCR5 were down-regulated on IKpDC. We also show that HIV-1-induced IKpDC depended on Toll-like receptor 7 (TLR7) activation. HIV-1 or TLR7 agonistexposed IKpDC induced apoptosis of the CD4(+) T cell line SupT1 via the TRAIL pathway. Furthermore, IFN-alpha produced after HIV-induced TLR7 stimulation was responsible for TRAIL expression and the down-regulation of both CXCR4 and CCR5 by IKpDC. In contrast, activation and migration markers were not regulated by IFN-alpha. Finally, IFN-alpha increased the survival of IKpDC. We characterized a subset of pDC with a killer activity that is activated by endosomal-associated viral RNA and not by infection.
Hardy
Andrew W
AW
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Graham
David R
DR
Shearer
Gene M
GM
Herbeuval
Jean-Philippe
JP
D000143:Acids / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016898:Interferon-alpha / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
D000143:Acids; D016898:Interferon-alpha; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C495348:TLR7 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D051199:Toll-Like Receptor 7