A functional interaction between plasmacytoid dendritic cells (pDCs) and CD169+ macrophages in the bone marrow regulates pDCs production of type I interferon during severe malaria

Abstract

Abstract While type I interferon (IFN-I) is central to antiviral immunity, it can also promote pathology in bacterial and parasitic infections, and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) are able to produce 1,000× more IFN-I than any other cell upon sensing of nucleic acid ligands by TLR7 and TLR9. pDCs can obtain their ligands via direct cell-cell interactions, yet what regulates these interactions and whether pDCs need to receive additional signals to secrete IFN-I is unknown. Using a mouse model of severe malaria, we showed that pDCs initiate IFN-I production in the bone marrow (BM) of infected mice, and that this required CD169+ macrophages (MPs). IFN-I production by pDCs was also dependent on TLR7 and STING sensing in pDCs and CD169+ MPs, respectively. Through intravital microscopy (IVM), we further revealed that pDCs arrest and form clusters with CD169+MPs in the BM of malaria infected mice when peak IFN-I production occurs. Here, we hypothesize that pDC-MP interactions are required to license pDCs to produce IFN-I. We found that pDCs fail to arrest and form clusters with MPs in Tlr7−/− mice, and that blocking chemotaxis prevents pDC-MP interactions and subsequent IFN-I production, consistent with our hypothesis. Interestingly, while pDCs do not make IFN-I in STING-deficient mice, they still arrest and cluster around MPs. These clusters are much larger than in WT mice, suggesting that pDCs fail to receive another STING-dependent signal. Collectively, these results support a model in which pDC production of IFN-I is tightly regulated through a functional interaction with CD169+ MPs providing activating ligands and stimulatory signals. Targeting this interaction may represent a novel way to tune levels of IFN-I produced by pDCs.