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Primary infection and reactivation may cause severe diseases in immunocompetent and immunosuppressed individuals. This study investigated the role of human plasmacytoid dendritic cells (pDC<\/jats:styled-content>) in the activation of natural killer (NK<\/jats:styled-content>) cells for the control of herpesviral infections. Within peripheral blood mononuclear cells, UV<\/jats:styled-content>\u2010inactivated HSV<\/jats:styled-content>\u20101 and C<\/jats:styled-content>pG<\/jats:styled-content>\u2010A<\/jats:styled-content> induced CD<\/jats:styled-content>69 up\u2010regulation on NK<\/jats:styled-content> cells, whereas infectious HSV<\/jats:styled-content>\u20101 was particularly active in inducing NK<\/jats:styled-content> cell effector functions interferon\u2010\u03b3<\/jats:italic> (IFN<\/jats:styled-content>\u2010\u03b3<\/jats:italic>) secretion and degranulation. The pDC<\/jats:styled-content>\u2010derived IFN<\/jats:styled-content>\u2010\u03b1<\/jats:italic> significantly contributed to NK<\/jats:styled-content> cell activation, as evident from neutralization and cell depletion experiments. In addition, monocyte\u2010derived tumour necrosis factor\u2010\u03b1<\/jats:italic> (TNF<\/jats:styled-content>\u2010\u03b1<\/jats:italic>) induced after exposure to infectious HSV<\/jats:styled-content>\u20101 was found to stimulate IFN<\/jats:styled-content>\u2010\u03b3<\/jats:italic> secretion. A minority of monocytes was shown to be non\u2010productively infected in experiments using fluorescently labelled viruses and quantitative PCR<\/jats:styled-content> analyses. HSV<\/jats:styled-content>\u20101\u2010exposed monocytes up\u2010regulated classical HLA<\/jats:styled-content>\u2010ABC<\/jats:styled-content> and non\u2010classical HLA<\/jats:styled-content>\u2010E<\/jats:styled-content> molecules at the cell surface in an IFN<\/jats:styled-content>\u2010\u03b1<\/jats:italic>\u2010dependent manner, whereas stress molecules MICA<\/jats:styled-content>\/B<\/jats:styled-content> were not induced. Notably, depletion of monocytes reduced NK<\/jats:styled-content> cell effector functions induced by infectious HSV<\/jats:styled-content>\u20101 (P<\/jats:italic>\u00a0<\u00a00\u00b705). Altogether, our data suggest a model in which HSV<\/jats:styled-content>\u20101\u2010stimulated pDC<\/jats:styled-content> and monocytes activate NK<\/jats:styled-content> cells via secretion of IFN<\/jats:styled-content>\u2010\u03b1<\/jats:italic> and TNF<\/jats:styled-content>\u2010\u03b1<\/jats:italic>. In addition, infection of monocytes induces NK<\/jats:styled-content> cell effector functions via TNF<\/jats:styled-content>\u2010\u03b1<\/jats:italic>\u2010dependent and TNF<\/jats:styled-content>\u2010\u03b1<\/jats:italic>\u2010independent mechanisms. Hence, pDC<\/jats:styled-content> and monocytes, which are among the first cells infiltrating herpetic lesions, appear to have important bystander functions for NK<\/jats:styled-content> cells to control these viral infections.<\/jats:p>","DOI":"10.1111\/imm.12337","type":"journal-article","created":{"date-parts":[[2014,6,18]],"date-time":"2014-06-18T23:32:14Z","timestamp":1403134334000},"page":"588-600","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Both plasmacytoid dendritic cells and monocytes stimulate natural killer cells early during human herpes simplex virus type 1 infections"],"prefix":"10.1111","volume":"143","author":[{"given":"Karin","family":"Vogel","sequence":"first","affiliation":[{"name":"Institute of Clinical and Molecular Virology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg Erlangen 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