HIV-1-derived lentiviral vectors directly activate plasmacytoid dendritic cells, which in turn induce the maturation of myeloid dendritic cells.
Lentiviral vectors (LV) can induce type I interferon (IFN I) production from murine plasmacytoid dendritic cells (pDC), but not myeloid (my)DC. Here, we investigated whether this mechanism is conserved in human DC. MyDC and pDC were isolated from peripheral blood and transduced with increasing vector concentrations. Compared with in vitro differentiated monocyte-derived DC, the transduction efficiency of peripheral blood DC was low (ranging from <1% to 45%), with pDC showing the lowest susceptibility to LV transduction. Phenotype and function of myDC were not directly modified by LV transduction; by contrast, pDC produced significant levels of IFN-α and tumor necrosis factor-α. pDC activation was dependent on functional vector particles and was mediated by Toll-like receptor 7/9 triggering. Coculture of myDC with pDC in the presence of LV resulted in myDC activation, with CD86 up-regulation and interleukin-6 secretion. These findings demonstrate that the induction of transgene-specific immunity is triggered by an innate immune response with pDC activation and consequent myDC maturation, a response that closely resembles the one induced by functional viruses. This information is important to design strategies aimed at using LV in humans for gene therapy, where adverse immune responses must be avoided, or for cancer immunotherapy, where inducing immunity is the goal.
Rossetti
Maura
M
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) , Department of Regenerative Medicine, Stem Cells and Gene Therapy, Via Olgettina 58, Milan, Italy.
Gregori
Silvia
S
Hauben
Ehud
E
Brown
Brian D
BD
Sergi
Lucia Sergi
LS
Naldini
Luigi
L
Roncarolo
Maria-Grazia
MG
D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism*; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D022423:Myeloid Cells / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D016898:Interferon-alpha; D015850:Interleukin-6; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha