Human plasmacytoid dendritic cells regulate IFN-α production through activation-induced splicing of IL-18Rα

A novel IL-18R isoform and activation-induced splicing of IL-18R down-modulates IFN production in human pDCs upon viral exposure. IFN- production by pDCs regulates host protection against viruses and is implicated in autoimmune pathology. Human pDCs express high levels of IL-18R, but little is known of its role in pDC function. We report that IL-18R signaling negatively regulates IFN- production through activation-induced splicing of IL-18R in human pDCs. Our data reveal two distinct isoforms of IL-18R in human pDCs: the known, full-length receptor (IL-18R1) and a novel, truncated variant (IL-18R2), which functions as a molecular decoy that competitively inhibits the canonical IL-18R1/IL-18R signaling pathway. Whereas NK cells and pDCs both express IL-18R1, pDCs express significantly higher levels of IL-18R2, resulting in differential responses of these populations to IL-18. Flu exposure increases IL-18R1 expression in pDCs, and the blocking of IL-18R enhances pDC production of IFN- and IP-10; thus, pDCs use activation-induced splicing to regulate IFN- production in response to flu. These data demonstrate that IL-18R modulates IFN- release by human pDCs and suggest that IL-18R signaling may represent a promising therapeutic target.