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.

Download full-text


Available from: Bruce Beutler,
20 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Here, we examine the mechanism by which plasmacytoid dendritic cells (pDCs) and type I interferons promote humoral autoimmunity. In an amyloid-induced experimental autoimmune model, neutrophil depletion enhanced anti-nuclear antibody development, which correlated with heightened IFN-γ production by natural killer (NK) cells. IFN-α/β produced by pDCs activated NK cells via IL-15 induction. Neutrophils released reactive oxygen species (ROS), which negatively modulated the levels of IL-15, thereby inhibiting IFN-γ production. Mice deficient in NADPH oxidase 2 produced increased amounts of IFN-γ and developed augmented titers of autoantibodies. Both the pDC-IFN-α/β pathway and IFN-γ were indispensable in stimulating humoral autoimmunity. Male NZB/W F1 mice expressed higher levels of superoxide than their female lupus-prone siblings, and depletion of neutrophils resulted in spontaneous NK cell and autoimmune B cell activation. Our findings suggest a regulatory role for neutrophils in vivo and highlight the importance of an NK-IFN-γ axis downstream of the pDC-IFN-α/β pathway in systemic autoimmunity. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 08/2015; 12(7). DOI:10.1016/j.celrep.2015.07.021 · 8.36 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Plasmacytoid dendritic cells (pDCs) have long been implicated in the pathogenesis of lupus. However, this conclusion has been largely based on a correlative link between the copious production of IFN-α/β by pDCs and the IFN-α/β "signature" often seen in human lupus patients. The specific contribution of pDCs to disease in vivo has not been investigated in detail. For this reason, we generated a strain of BXSB lupus-prone mice in which pDCs can be selectively depleted in vivo. Early, transient ablation of pDCs before disease initiation resulted in reduced splenomegaly and lymphadenopathy, impaired expansion and activation of T and B cells, reduced antibodies against nuclear autoantigens and improved kidney pathology. Amelioration of pathology coincided with decreased transcription of IFN-α/β-induced genes in tissues. PDC depletion had an immediate impact on the activation of immune cells, and importantly, the beneficial effects on pathology were sustained even though pDCs later recovered, indicating an early pDC contribution to disease. Together, our findings demonstrate a critical function for pDCs during the IFN-α/β-dependent initiation of autoimmune lupus and point to pDCs as an attractive therapeutic target for the treatment of SLE.
    Journal of Experimental Medicine 09/2014; 211(10). DOI:10.1084/jem.20132620 · 12.52 Impact Factor
  • Source
    • "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. "
    Wei Cao ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Plasmacytoid dendritic cells (pDCs) were initially identified as the prominent natural type I interferon-producing cells during viral infection. Over the past decade, the aberrant production of interferon α/β by pDCs in response to self-derived molecular entities has been critically implicated in the pathogenesis of systemic lupus erythematosus and recognized as a general feature underlying other autoimmune diseases. On top of imperative studies on human pDCs, the functional involvement and mechanism by which the pDC-interferon α/β pathway facilitates the progression of autoimmunity have been unraveled recently from investigations with several experimental lupus models. This article reviews correlating information obtained from human in vitro characterization and murine in vivo studies and highlights the fundamental and multifaceted contribution of pDCs to the pathogenesis of systemic autoimmune manifestation.
    04/2014; 5(2):212. DOI:10.4172/2155-9899.1000212
Show more