Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells

Abstract

The natural interferon (IFN)‐producing cell is now known to be identical to the plasmacytoid dendritic cell (PDC). These are Lin⁻, CD123⁺, CD11c⁻, and human leukocyte antigen‐DR⁺ cells that secrete large amounts of IFN‐α (1–2 IU/cell) when stimulated by enveloped viruses such as herpes simplex virus. In the current study, we have evaluated chemokine expression by virally stimulated PDC. Up‐regulation of mRNA for CCL4, CCL3, CCL5, CCL2, and CXC chemokine ligand (CXCL)10 in herpes simplex virus‐stimulated PDC was detected by RNAse protection assays. In contrast, PDC‐depleted peripheral blood mononuclear cells did not up‐regulate these mRNA species upon viral stimulation. Enzyme‐linked immunosorbent assay and/or intracellular flow cytometry confirmed production of these proteins, and studies indicated overlapping production of IFN‐α and the other cytokines/chemokines by PDC. Endocytosis plays a critical role in chemokine induction, as disruption of the pathway inhibits the response. However, transcription of viral genes is not required for chemokine induction. Autocrine IFN‐α signaling in the PDC could account for a portion of the CXCL10 and CCL2 production in virally stimulated PDC but was not responsible for the induction of the other chemokines. To evaluate the functional role of the chemokines, chemotaxis assays were performed using supernatants from virally stimulated PDC. Activated T cells and natural killer cells, but not naïve T cells, were preferentially recruited by these PDC supernatants. Migration was subsequently inhibited by addition of neutralizing antibody to CCL4 and CXCL10. We hypothesize that virally induced chemokine production plays a pivotal role in the homing of leukocytes to PDC.