Research ArticleDENDRITIC CELLS

Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells

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Science Immunology  02 Apr 2021:
Vol. 6, Issue 58, eabc7302
DOI: 10.1126/sciimmunol.abc7302

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Touched by a plasmacytoid dendritic cell

Plasmacytoid dendritic cells (pDCs) are crucial to generating strong antiviral immune responses, yet it is unclear how these cells recognize viral infections. Yun et al. tested the cytokine production of human pDCs in response to free cytomegalovirus (CMV) or CMV-infected cells in vitro. They found that pDCs generated robust type I and III interferon responses to CMV-infected cells but not free CMV. These pDC interferon responses were long-lasting and facilitated strong antiviral NK cell responses. Elevated interferons and pDC activation were confirmed in patients with active CMV infections. Similar pDC responses were seen with influenza-infected cells. Together, these data suggest a more general phenomenon whereby antiviral immune responses are supported by the direct recognition of virally infected cells by pDCs.

Abstract

Plasmacytoid dendritic cells (pDCs) can rapidly produce interferons and other soluble factors in response to extracellular viruses or virus mimics such as CpG-containing DNA. pDCs can also recognize live cells infected with certain RNA viruses, but the relevance and functional consequences of such recognition remain unclear. We studied the response of primary DCs to the prototypical persistent DNA virus, human cytomegalovirus (CMV). Human pDCs produced high amounts of type I interferon (IFN-I) when incubated with live CMV-infected fibroblasts but not with free CMV; the response involved integrin-mediated adhesion, transfer of DNA-containing virions to pDCs, and the recognition of DNA through TLR9. Compared with transient polyfunctional responses to CpG or free influenza virus, pDC response to CMV-infected cells was long-lasting, dominated by the production of IFN-I and IFN-III, and lacked diversification into functionally distinct populations. Similarly, pDC activation by influenza-infected lung epithelial cells was highly efficient, prolonged, and dominated by interferon production. Prolonged pDC activation by CMV-infected cells facilitated the activation of natural killer cells critical for CMV control. Last, patients with CMV viremia harbored phenotypically activated pDCs and increased circulating IFN-I and IFN-III. Thus, recognition of live infected cells is a mechanism of virus detection by pDCs that elicits a unique antiviral immune response.

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