Summary Type I interferon (IFN) is critical for controlling pathogen infection; however, its regulatory mechanisms in plasmacytoid cells (pDCs) still remain unclear. Here, we have shown that nucleic acid sensors cGAS-, STING-, MDA5-, MAVS-, or transcription factor IRF3-deficient mice produced high amounts of type I IFN-α and IFN-β (IFN-α/β) in the serum and were resistant to lethal plasmodium yoelii YM infection. Robust IFN-α/β production was abolished when gene encoding nucleic acid sensor TLR7, signaling adaptor MyD88, or transcription factor IRF7 was ablated or pDCs were depleted. Further, we identified SOCS1 as a key negative regulator to inhibit MyD88-dependent type I IFN signaling in pDCs. Finally, we have demonstrated that pDCs, cDCs, and macrophages were required for generating IFN-α/β-induced subsequent protective immunity. Thus, our findings have identified a critical regulatory mechanism of type I IFN signaling in pDCs and stage-specific function of immune cells in generating potent immunity against lethal YM infection. Graphical Abstract Highlights • cGAS functions as a DNA sensor in vivo for detecting malaria genomic DNA • STING- and MAVS-mediated signaling induces a negative regulator SOCS1 expression • SOCS1 inhibits MyD88-mediated type I IFN signaling in pDCs • Type I IFN produced by pDCs activates cDCs and macrophages for adaptive immunity Malaria is a worldwide deadly infectious disease; how type I IFN signaling is regulated in response to malaria infection remains poorly understood. Yu et al. identify a cross-regulatory mechanism of two type I IFN signaling pathways in plasmacytoid DCs, which is critical for generating protective immunity against lethal malaria infection.
【저자키워드】 innate immune response, plasmacytoid dendritic cells, Malaria infection, Type I IFN signaling,