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Slc15a4, AP-3, and Hermansky-Pudlak Syndrome Proteins Are Required for Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells

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Slc15a4, AP-3, and Hermansky-Pudlak Syndrome Proteins Are Required for Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells Amanda L. Blasius, Carrie N. Arnold, Philippe Georgel1, Sophie Rutschmann2, Yu Xia, Pei Lin, Charles Ross, Xiaohong Li, Nora G. Smart, and Bruce Beutler3 Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037 Contributed by Bruce Beutler, September 17, 2010 (sent for review September 16, 2010) Despite their low frequency, plasmacytoid dendritic cells (pDCs) abrogate TLR7 and TLR9 signaling in pDCs. We show that lyso- produce most of the type I IFN that is detectable in the blood some-related organelle (LRO) trafficking and biogenesis proteins, following viral infection. The endosomal Toll-like receptors (TLRs) such as adapter-related protein complex-3 (AP-3) and Hermansky- TLR7 and TLR9 are required for pDCs, as well as other cell types, to Pudlack syndrome (HPS) proteins of the biogenesis of lysosome- sense viral nucleic acids, but the mechanism by which signaling related organelle complex (BLOC)-1 and BLOC-2 groups, are through these shared receptors results in the prodigious production specifically required for type I IFN and cytokine production in of type I IFN by pDCs is not understood. We designed a genetic pDCs. Moreover, Slc15a4, an obscure solute channel protein, is screen to identify proteins required for the development and essential for TLR-mediated signaling in pDCs. Our data reveal a specialized function of pDCs. One phenovariant, which we named specialized membrane trafficking mechanism necessary for TLR feeble, showed abrogation of both TLR-induced type I IFN and pro- signaling in pDCs, which could explain their unique responses to inflammatory cytokine production by pDCs, while leaving TLR re- viral infection. sponses intact in other cells. The feeble phenotype was mapped to a mutation in Slc15a4, which encodes the peptide/histidine trans- Results porter 1 (PHT1) and has not previously been implicated in pDC func- Forward Genetic Screen to Identify Proteins with Nonredundant Roles fi feeble tion. The identi cation of the mutation led to our subsequent in Type I IFN Production by pDCs. To detect defects in pDC de- observations that AP-3, as well as the BLOC-1 and BLOC-2 Herman- velopment or function, we injected randomly mutagenized mice sky-Pudlak syndrome proteins are essential for pDC signaling with the TLR9 agonist CpG-A mixed with the cationic lipid through TLR7 and TLR9. These proteins are not necessary for TLR7 DOTAP, and measured type I IFN in serum six hours later. As or TLR9 signaling in conventional DCs and thus comprise a mem- expected, mice with defects in TLR9 signaling or type I IFN fi − − brane traf cking pathway uniquely required for endosomal TLR production, Tlr9 / , Myd88poc/poc, Irak4otiose/otiose, Unc93b13d/3d, − − signaling in pDCs. and Ifnar1 / , failed to produce detectable type I IFN following CpG challenge (Fig. 1A). Among more than 4,500 third genera- IMMUNOLOGY adapter protein 3 | lysosome-related organelle | solute carrier | tion (G3) C57BL/6J mice homozygous for random ENU- type I interferon | vesicular trafficking induced germline mutations produced as previously described (12), mice derived from 5 different pedigrees failed to produce lasmacytoid dendritic cells (pDCs) are a rare subset of DCs serum type I IFN after CpG-A challenge (Fig. 1B). The first mu- Pfound in the blood and peripheral lymphoid organs. They tation, denoted CpG6, also impaired TNF production by perito- differ from conventional DCs in that they are derived from neal macrophages in response to CpG-B oligodeoxynucleotide lymphoid rather than myeloid precursors and by differences in stimulation. Tlr9 was therefore sequenced, which revealed a G→A cell-surface markers. Despite their rarity, pDCs are the source of transition in exon 2 of Tlr9 (Fig. S1A). A second mutation, named most of the type I IFN produced in vivo during most viral inept, was found to affect not only pDC responses to CpG-A, but infections (1–3). pDCs also secrete proinflammatory cytokines also to resiquimod. The inept mutation, an A→G transition in exon and chemokines that initiate the innate immune response and 4ofIrf7, was identified by whole genome sequencing using the help orchestrate the subsequent adaptive immune response. Applied Biosystems SOLiD 3+ sequencing platform and verified However, their role in host defense remains uncertain because by Sanger dideoxynucleotide sequencing (Fig. S1B). The gemini depletion studies have not yet demonstrated a clear susceptibility mutation, which was initially identified in a screen for proteins phenotype in any viral infection (3, 4). required for the innate immune response to MCMV infection, was pDCs are activated upon engagement of Toll-like receptors subsequently found to also abrogate the type I IFN response to in (TLRs), which recognize molecular signatures of microbes in- vivo CpG-A challenge. In addition to these phenotypes, gemini cluding viruses (reviewed in ref. 5). In particular, ssRNA and mice were characterized by marked neutrophilia and a paucity of ssDNA engage TLR7 and TLR9, respectively, within acidified endosomal compartments. Signaling through both of these recep- tors is MyD88- and IRAK-4–dependent, and in pDCs, additionally Author contributions: A.L.B. and B.B. designed research; A.L.B., C.N.A., P.G., S.R., P.L., C.R., dependent on inhibitor κ-B kinase-α (IKKα), osteopontin, and IFN and X.L. performed research; A.L.B., Y.X., and B.B. analyzed data; and A.L.B., C.N.A., regulator factor 7 (IRF7) for type I IFN production (6, 7). At least N.G.S., and B.B. wrote the paper. three chaperone molecules (PRAT4A, GP96, and UNC93B) are The authors declare no conflict of interest. 1 necessary for trafficking TLR7 and TLR9 to their correct sub- Present address: Laboratoire d’Immunogénétique Moléculaire Humaine, Centre de Re- – cherche d’Immunologie et d’Hématologie, Faculté de Médecine, 4 rue Kirschleger, Stras- cellular location in most or all cell types (8 10); a specialized bourg, Cedex 67085, France. fi traf cking system for TLRs in pDCs, which may be required for 2Present address: Imperial College London, Faculty of Medicine, Du Cane Road, London TLR-induced type I IFN production, has been proposed but not W12 0NN, United Kingdom. described (11). 3To whom correspondence should be addressed: E-mail: [email protected]. Here, we describe a series of mutations, detected in an in vivo This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. screen for proteins required for pDC function, which selectively 1073/pnas.1014051107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1014051107 PNAS | November 16, 2010 | vol. 107 | no. 46 | 19973–19978 Downloaded by guest on October 2, 2021 1000 with TLR7 or TLR9 ligands (Fig. 2A) despite having normal A 900 800 frequencies of splenic pDCs (Fig. 2C). pDCs also develop in vitro 700 in Flt3L-treated bone marrow cultures from feeble mice (Fig. 2C); 600 α 500 however, these cells do not secrete type I IFN or TNF- , IL-12, or 400 IL-6 in response to TLR7 and TLR9 ligands (Fig. 2 A and B). 300 200 pDCs were enriched to high purity from the Flt3L cultures to 100 prevent detection of cytokines generated by other cell pop- Serum Type I IFN (U/ml) Serum Type 0 WT TLR9-/- poc otiose 3d IFNAR1-/- dom ulations. The defect in type I IFN production by feeble pDCs is not 400 due to an inability to secrete type I IFN-because Ifna transcripts B and intracellular type I IFN protein could not be detected in in 300 vitro-generated feeble pDCs, even when exogenous type I IFN was 200 added to circumvent the requirement for the IFN feed-forward loop (Fig. 3 A and B). Uptake of CpG by feeble pDCs is normal, 100 Type I IFN (U/ml) suggesting that the feeble defect occurs after TLR ligands are in- 0 ternalized (Fig. 3C). G3 CpG6 inept gemini meager feeble In contrast to our observation that pDCs from feeble mice fail Fig. 1. Identification of mutants with in vivo defects in pDC type I IFN pro- to respond to TLR ligands, we found that conventional dendritic duction. Mice were injected with the TLR9 ligand CpG-A along with DOTAP cells (cDCs) from these mutants (generated in vitro from GM- and serum type I IFN levels measured six hours later. The screen was validated CSF-treated bone marrow cells) produce near normal amounts of by testing mice with mutations in genes known to be essential for the type I α − − TNF- following stimulation with all TLR stimuli, including IFN response to CpG-A. Tlr9 / , MyD88poc/poc, Irak4otiose/otiose, Unc93b13d/3d, − − TLR7 and TLR9 ligands (Fig. S2A). Furthermore, TRIF-dependent Ifnar1 / , and Stat1dom/dom mice all displayed little to no serum type I IFN (A). Screening ENU-mutagenized G3 mice revealed five unique pedigrees with signaling through TLR4 is intact in cDCs from feeble mice (Fig. defects in the CpG-induced type I IFN response. These mutations included S2B). Finally, feeble cDCs transfected with double-stranded DNA alleles in Tlr9 (CpG6), Irf7 (inept), and Irf8 (gemini). Gemini and meager mice produce IFN, demonstrating that DNA sensing through DNA cy- were assayed on a different day (B). All error bars represent SEM. tosolic sensors is intact in these mice (Fig. S2C). Collectively, these observations show that the feeble mutation selectively impairs the ability of pDCs, but not cDCs, to respond to TLR ligands and monocytes and mature macrophages (Fig. S1C). The MCMV produce IFN. susceptibility and cellular phenotypes were mapped to chromo- some 8 by bulk segregation analysis (BSA) (13) (Fig. S1D), and Mapping and Identification of the feeble Mutation. We mapped the candidate gene sequencing revealed a nonsense mutation in the feeble phenotype by crossing homozygous mutant mice to C3H/ DNA binding domain of IRF8.
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