Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells

Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2010; 107(46):19973-8. DOI: 10.1073/pnas.1014051107
Source: PubMed


Despite their low frequency, plasmacytoid dendritic cells (pDCs) produce most of the type I IFN that is detectable in the blood following viral infection. The endosomal Toll-like receptors (TLRs) TLR7 and TLR9 are required for pDCs, as well as other cell types, to sense viral nucleic acids, but the mechanism by which signaling through these shared receptors results in the prodigious production of type I IFN by pDCs is not understood. We designed a genetic screen to identify proteins required for the development and specialized function of pDCs. One phenovariant, which we named feeble, showed abrogation of both TLR-induced type I IFN and proinflammatory cytokine production by pDCs, while leaving TLR responses intact in other cells. The feeble phenotype was mapped to a mutation in Slc15a4, which encodes the peptide/histidine transporter 1 (PHT1) and has not previously been implicated in pDC function. The identification of the feeble mutation led to our subsequent observations that AP-3, as well as the BLOC-1 and BLOC-2 Hermansky-Pudlak syndrome proteins are essential for pDC signaling through TLR7 and TLR9. These proteins are not necessary for TLR7 or TLR9 signaling in conventional DCs and thus comprise a membrane trafficking pathway uniquely required for endosomal TLR signaling in pDCs.

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    • "During the early phase of mouse cytomegalovirus infection, pDCs produce IFN-I and promote transient NK cell activation and cytotoxicity in vivo (Swiecki et al., 2010). To investigate the role of pDC-dependent IFN-I pathway in NK cell activation, we inoculated amyloid into Ifnar À/À mice as well as feeble mice, which carry a mutant Slc15a4 gene and are selectively defective in IFN production by pDCs (Blasius et al., 2010). Both strains produced significantly lower IFN-g than WT mice (Figure 5A), suggesting a prominent role of IFNa/b produced by pDCs in provoking NK cell activation. "
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    • "It was concluded that pDCs are critical for the pathogenesis of lupus based on the limited production of autoantibodies against nuclear antigens (Baccala et al., 2013). In the same study, the phenotype of IRF8-deficient mice was similar to that of Slc15a4-deficient mice, which harbor pDCs that have impaired production of IFN-/ and inflammatory cytokines (Blasius et al., 2010). "
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    • "A recent study suggested that, in murine pDCs, DNA-containing ICs are transported by a process called microtubule-associated protein 1A/1 B-LC3–associated phagocytosis primarily via the convergence of phagocytic and autophagic pathways to induce IFN production [46]. This pathway unexpectedly diverges from the membrane trafficking pathway involving AP-3, which is critical for TLR9 signaling induced by viruses and synthetic nucleic acid agonists [24,26] (Figure 1). Whether a comparable signaling compartment is preserved in human pDCs and thus can be specifically targeted remains to be seen. "
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