Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination (original) (raw)

• Coffman, R. L., Sher, A. & Seder, R. A. Vaccine adjuvants: putting innate immunity to work. Immunity 33, 492–503 (2010).
  CAS PubMed Central PubMed Google Scholar
• Pulendran, B. & Ahmed, R. Immunological mechanisms of vaccination. Nature Immunol. 131, 509–517 (2011).
  Google Scholar
• Plotkin, S. A. Vaccines: correlates of vaccine-induced immunity. Clin. Infect. Dis. 47, 401–409 (2008).
  PubMed Google Scholar
• Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).
  CAS PubMed Central PubMed Google Scholar
• Pichlmair, A. & Reis e Sousa, C. Innate recognition of viruses. Immunity 27, 370–383 (2007).
  CAS PubMed Google Scholar
• Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).
  CAS PubMed Google Scholar
• Barbalat, R., Ewald, S. E., Mouchess, M. L. & Barton, G. M. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185–214 (2011).
  CAS PubMed Google Scholar
• Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nature Rev. Immunol. 10, 826–837 (2010).
  CAS Google Scholar
• Blasius, A. L. & Beutler, B. Intracellular Toll-like receptors. Immunity 32, 305–315 (2010).
  CAS PubMed Google Scholar
• Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011).
  CAS PubMed Google Scholar
• Loo, Y. M. & Gale, M. Jr. Immune signaling by RIG-I-like receptors. Immunity 34, 680–692 (2011).
  CAS PubMed Central PubMed Google Scholar
• Kadowaki, N. et al. Subsets of human dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194, 863–869 (2001).
  CAS PubMed Central PubMed Google Scholar
• Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol. 5, 987–995 (2004).
  CAS Google Scholar
• Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunol. 11, 373–384 (2010).
  CAS Google Scholar
• Schlee, M. & Hartmann, G. The chase for the RIG-I ligand — recent advances. Mol. Ther. 18, 1254–1262 (2010).
  CAS PubMed Central PubMed Google Scholar
• Ablasser, A. et al. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nature Immunol. 10, 1065–1072 (2009).
  CAS Google Scholar
• Chiu, Y.-H., MacMillan, J. B. & Chen, Z. J. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138, 576–591 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kato, H. et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J. Exp. Med. 205, 1601–1610 (2008).
  CAS PubMed Central PubMed Google Scholar
• Malathi, K., Dong, B., Gale, M. & Silverman, R. H. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448, 816–819 (2007).
  CAS PubMed Central PubMed Google Scholar
• Venkataraman, T. et al. Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. J. Immunol. 178, 6444–6455 (2007).
  CAS PubMed Google Scholar
• Satoh, T. et al. LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc. Natl Acad. Sci. USA 107, 1512–1517 (2010).
  CAS PubMed Central PubMed Google Scholar
• Monroe, K. M., McWhirter, S. M. & Vance, R. E. Identification of host cytosolic sensors and bacterial factors regulating the type I interferon response to Legionella pneumophila. PLoS Pathog. 5, e1000665 (2009).
  PubMed Central PubMed Google Scholar
• Li, X. D. et al. Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis. Proc. Natl Acad. Sci. USA 108, 17390–17395 (2011).
  CAS PubMed PubMed Central Google Scholar
• Poeck, H. et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1β production. Nature Immunol. 11, 63–69 (2010).
  CAS Google Scholar
• Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Zhong, B. et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538–550 (2008).
  CAS PubMed Google Scholar
• Oshiumi, H., Sakai, K., Matsumoto, M. & Seya, T. DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-β-inducing potential. Eur. J. Immunol. 40, 940–948 (2010).
  CAS PubMed Google Scholar
• Zhang, Z. et al. DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 34, 866–878 (2011).
  CAS PubMed Central PubMed Google Scholar
• Miyashita, M., Oshiumi, H., Matsumoto, M. & Seya, T. DDX60, a DEXD/H box helicase, is a novel antiviral factor promoting RIG-I-like receptor-mediated signaling. Mol. Cell. Biol. 31, 3802–3819 (2011).
  CAS PubMed Central PubMed Google Scholar
• Kim, T. et al. Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. Proc. Natl Acad. Sci. USA 107, 15181–15186 (2010).
  CAS PubMed PubMed Central Google Scholar
• Zhang, Z. et al. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nature Immunol. 12, 959–965 (2011).
  CAS Google Scholar
• Zhang, Z., Yuan, B., Lu, N., Facchinetti, V. & Liu, Y. J. DHX9 pairs with IPS-1 to sense double-stranded RNA in myeloid dendritic cells. J. Immunol. 187, 4501–4508 (2011).
  CAS PubMed Google Scholar
• Elinav, E., Strowig, T., Henao-Mejia, J. & Flavell, R. A. Regulation of the antimicrobial response by NLR proteins. Immunity 34, 665–679 (2011).
  CAS PubMed Google Scholar
• Sabbah, A. et al. Activation of innate immune antiviral responses by Nod2. Nature Immunol. 10, 1073–1080 (2009).
  CAS Google Scholar
• Kanneganti, T. D. et al. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J. Biol. Chem. 281, 36560–36568 (2006).
  CAS PubMed Google Scholar
• Allen, I. C. et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 30, 556–565 (2009).
  CAS PubMed Central PubMed Google Scholar
• Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).
  CAS PubMed Central PubMed Google Scholar
• Keating, S. E., Baran, M. & Bowie, A. G. Cytosolic DNA sensors regulating type I interferon induction. Trends Immunol. 32, 574–581 (2011).
  CAS PubMed Google Scholar
• Burckstummer, T. et al. An orthogonal proteomic–genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nature Immunol. 10, 266–272 (2009).
  Google Scholar
• Fernandes-Alnemri, T., Yu, J.-W., Datta, P., Wu, J. & Alnemri, E. S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509–513 (2009).
  CAS PubMed Central PubMed Google Scholar
• Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009).
  CAS PubMed Central PubMed Google Scholar
• Roberts, T. L. et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323, 1057–1060 (2009).
  CAS PubMed Google Scholar
• Unterholzner, L. et al. IFI16 is an innate immune sensor for intracellular DNA. Nature Immunol. 11, 997–1004 (2010).
  CAS Google Scholar
• Kerur, N. et al. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi sarcoma-associated herpesvirus infection. Cell Host Microbe 9, 363–375 (2011).
  CAS PubMed Central PubMed Google Scholar
• Takaoka, A. et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501–505 (2007).
  CAS PubMed Google Scholar
• Kaiser, W. J., Upton, J. W. & Mocarski, E. S. Receptor-interacting protein homotypic interaction motif-dependent control of NF-κB activation via the DNA-dependent activator of IFN regulatory factors. J. Immunol. 181, 6427–6434 (2008).
  CAS PubMed Google Scholar
• Ishii, K. J. et al. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature 451, 725–729 (2008).
  CAS PubMed Google Scholar
• Yang, P. et al. The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a β-catenin-dependent pathway. Nature Immunol. 11, 487–494 (2010).
  CAS Google Scholar
• Burdette, D. L. et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478, 515–518 (2011).
  CAS PubMed Central PubMed Google Scholar
• Querec, T. et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J. Exp. Med. 203, 413–424 (2006).
  PubMed Central PubMed Google Scholar
• Gaucher, D. et al. Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. J. Exp. Med. 205, 3119–3131 (2008).
  CAS PubMed Central PubMed Google Scholar
• Querec, T. D. et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nature Immunol. 10, 116–125 (2009).
  CAS Google Scholar
• Caskey, M. et al. Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans. J. Exp. Med. 208, 2357–2366 (2011). References 51–53 illustrate how systems biology may help to deconstruct the mechanisms of action of current vaccines in humans.
  CAS PubMed Central PubMed Google Scholar
• Samuelsson, C. et al. Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection. J. Clin. Invest. 118, 1776–1784 (2008).
  CAS PubMed Central PubMed Google Scholar
• Delaloye, J. et al. Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. PLoS Pathog. 5, e1000480 (2009).
  PubMed Central PubMed Google Scholar
• Zhu, J., Martinez, J., Huang, X. & Yang, Y. Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-β. Blood 109, 619–625 (2007).
  CAS PubMed Central PubMed Google Scholar
• Quigley, M., Martinez, J., Huang, X. & Yang, Y. A critical role for direct TLR2–MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection. Blood 113, 2256–2264 (2009).
  CAS PubMed Central PubMed Google Scholar
• Martinez, J., Huang, X. & Yang, Y. Toll-like receptor 8- mediated activation of murine plasmacytoid dendritic cells by vaccinia viral DNA. Proc. Natl Acad. Sci. USA 107, 6442–6447 (2010).
  CAS PubMed PubMed Central Google Scholar
• Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).
  CAS PubMed Google Scholar
• Lund, J. M. et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl Acad. Sci. USA 101, 5598–5603 (2004).
  CAS PubMed PubMed Central Google Scholar
• Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nature Immunol. 5, 730–737 (2004).
  CAS Google Scholar
• Kato, H. et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23, 19–28 (2005).
  CAS PubMed Google Scholar
• Thomas, P. G. et al. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 30, 566–575 (2009).
  CAS PubMed Central PubMed Google Scholar
• Koyama, S. et al. Plasmacytoid dendritic cells delineate immunogenicity of influenza vaccine subtypes. Sci. Transl. Med. 2, 25ra24 (2010).
  PubMed Google Scholar
• Aoshi, T., Koyama, S., Kobiyama, K., Akira, S. & Ishii, K. J. Innate and adaptive immune responses to viral infection and vaccination. Curr. Opin. Virol. 1, 226–232 (2011).
  CAS PubMed Google Scholar
• Mancuso, G. et al. Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells. Nature Immunol. 10, 587–594 (2009).
  CAS Google Scholar
• von Meyenn, F. et al. Toll-like receptor 9 contributes to recognition of Mycobacterium bovis Bacillus Calmette-Guerin by Flt3-ligand generated dendritic cells. Immunobiology 211, 557–565 (2006).
  CAS PubMed Google Scholar
• Sander, L. E. et al. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 474, 385–389 (2011). This study supports the idea that bacterial nucleic acids may be recognized as a signal of microbial viability and may contribute to an enhanced adaptive immune response against the pathogen.
  CAS PubMed Central PubMed Google Scholar
• Liu, M. A. Immunologic basis of vaccine vectors. Immunity 33, 504–515 (2010).
  CAS PubMed Google Scholar
• Coban, C. et al. Novel strategies to improve DNA vaccine immunogenicity. Curr. Gene Ther. 11, 479–484 (2011).
  CAS PubMed Google Scholar
• Spies, B. et al. Vaccination with plasmid DNA activates dendritic cells via Toll-like receptor 9 (TLR9) but functions in TLR9-deficient mice. J. Immunol. 171, 5908–5912 (2003).
  CAS PubMed Google Scholar
• Babiuk, S. et al. TLR9−/− and TLR9+/+ mice display similar immune responses to a DNA vaccine. Immunology 113, 114–120 (2004).
  CAS PubMed Central PubMed Google Scholar
• Rottembourg, D. et al. Essential role for TLR9 in prime but not prime–boost plasmid DNA vaccination to activate dendritic cells and protect from lethal viral infection. J. Immunol. 184, 7100–7107 (2010).
  CAS PubMed Google Scholar
• Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009). This study identifies STING as an essential adapter protein in the signalling pathways of TBK1-activating cytosolic DNA sensors.
  CAS PubMed Central PubMed Google Scholar
• Mbow, M. L., De Gregorio, E., Valiante, N. M. & Rappuoli, R. New adjuvants for human vaccines. Curr. Opin. Immunol. 22, 411–416 (2010).
  CAS PubMed Google Scholar
• McKee, A. S. et al. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J. Immunol. 183, 4403–4414 (2009).
  CAS PubMed Google Scholar
• Marrack, P., McKee, A. S. & Munks, M. W. Towards an understanding of the adjuvant action of aluminium. Nature Rev. Immunol. 9, 287–293 (2009).
  CAS Google Scholar
• Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008).
  CAS Google Scholar
• Eisenbarth, S. C., Colegio, O. R., O'Connor, W., Sutterwala, F. S. & Flavell, R. A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008).
  CAS PubMed Central PubMed Google Scholar
• Spreafico, R., Ricciardi-Castagnoli, P. & Mortellaro, A. The controversial relationship between NLRP3, alum, danger signals and the next-generation adjuvants. Eur. J. Immunol. 40, 638–642 (2010).
  CAS PubMed Google Scholar
• Goto, N. et al. Local tissue irritating effects and adjuvant activities of calcium phosphate and aluminium hydroxide with different physical properties. Vaccine 15, 1364–1371 (1997).
  CAS PubMed Google Scholar
• Munks, M. W. et al. Aluminum adjuvants elicit fibrin-dependent extracellular traps in vivo. Blood 116, 5191–5199 (2010).
  CAS PubMed Central PubMed Google Scholar
• Kool, M. et al. Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J. Exp. Med. 205, 869–882 (2008).
  CAS PubMed Central PubMed Google Scholar
• Kool, M. et al. An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma. Immunity 34, 527–540 (2011).
  CAS PubMed Google Scholar
• Marichal, T. et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nature Med. 17, 996–1002 (2011).
  CAS PubMed Google Scholar
• Lore, K. et al. Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus- and HIV-1-specific T cell responses. J. Immunol. 171, 4320–4328 (2003).
  CAS PubMed Google Scholar
• Schulz, O. et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433, 887–892 (2005).
  CAS PubMed Google Scholar
• Jongbloed, S. L. et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J. Exp. Med. 207, 1247–1260 (2010).
  CAS PubMed Central PubMed Google Scholar
• Jelinek, I. et al. TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection. J. Immunol. 186, 2422–2429 (2011).
  CAS PubMed Google Scholar
• Poulin, L. F. et al. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8α+ dendritic cells. J. Exp. Med. 207, 1261–1271 (2010).
  CAS PubMed Central PubMed Google Scholar
• Trumpfheller, C. et al. The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc. Natl Acad. Sci. USA 105, 2574–2579 (2008).
  CAS PubMed PubMed Central Google Scholar
• Longhi, M. P. et al. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J. Exp. Med. 206, 1589–1602 (2009).
  CAS PubMed Central PubMed Google Scholar
• Stahl-Hennig, C. et al. Synthetic double-stranded RNAs are adjuvants for the induction of T helper 1 and humoral immune responses to human papillomavirus in rhesus macaques. PLoS Pathog. 5, e1000373 (2009).
  PubMed Central PubMed Google Scholar
• Kumar, H., Koyama, S., Ishii, K. J., Kawai, T. & Akira, S. Cutting edge: cooperation of IPS-1- and TRIF-dependent pathways in poly IC-enhanced antibody production and cytotoxic T cell responses. J. Immunol. 180, 683–687 (2008).
  CAS PubMed Google Scholar
• Tewari, K. et al. Poly(I:C) is an effective adjuvant for antibody and multi-functional CD4+ T cell responses to Plasmodium falciparum circumsporozoite protein (CSP) and αDEC-CSP in non human primates. Vaccine 28, 7256–7266 (2010).
  CAS PubMed Central PubMed Google Scholar
• Wang, Y., Cella, M., Gilfillan, S. & Colonna, M. Cutting edge: polyinosinic:polycytidylic acid boosts the generation of memory CD8 T cells through melanoma differentiation-associated protein 5 expressed in stromal cells. J. Immunol. 184, 2751–2755 (2010).
  CAS PubMed Google Scholar
• Russo, C. et al. Small molecule Toll-like receptor 7 agonists localize to the MHC class II loading compartment of human plasmacytoid dendritic cells. Blood 117, 5683–5691 (2011).
  CAS PubMed Google Scholar
• Levy, O., Suter, E. E., Miller, R. L. & Wessels, M. R. Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells. Blood 108, 1284–1290 (2006).
  CAS PubMed Central PubMed Google Scholar
• Hamm, S. et al. Immunostimulatory RNA is a potent inducer of antigen-specific cytotoxic and humoral immune response in vivo. Int. Immunol. 19, 297–304 (2007).
  CAS PubMed Google Scholar
• Zhang, W. W. & Matlashewski, G. Immunization with a Toll-like receptor 7 and/or 8 agonist vaccine adjuvant increases protective immunity against Leishmania major in BALB/c mice. Infect. Immun. 76, 3777–3783 (2008).
  CAS PubMed Central PubMed Google Scholar
• Rajagopal, D. et al. Plasmacytoid dendritic cell-derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists. Blood 115, 1949–1957 (2010).
  CAS PubMed Central PubMed Google Scholar
• Wille-Reece, U. et al. HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. Proc. Natl Acad. Sci. USA 102, 15190–15194 (2005).
  CAS PubMed PubMed Central Google Scholar
• Kastenmuller, K. et al. Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets. J. Clin. Invest. 121, 1782–1796 (2011). References 102 and 103 show how optimizing the formulation of agonists for nucleic acid sensors may affect quantitative and qualitative aspects of the response to subunit vaccines adjuvanted with such molecules.
  CAS PubMed Central PubMed Google Scholar
• Huang, X. & Yang, Y. Targeting the TLR9–MyD88 pathway in the regulation of adaptive immune responses. Expert Opin. Ther. Targets 14, 787–796 (2010).
  CAS PubMed Central PubMed Google Scholar
• Campbell, J. D. et al. CpG-containing immunostimulatory DNA sequences elicit TNF-α-dependent toxicity in rodents but not in humans. J. Clin. Invest. 119, 2564–2576 (2009).
  CAS PubMed Central PubMed Google Scholar
• Wagner, M. et al. IL-12p70-dependent Th1 induction by human B cells requires combined activation with CD40 ligand and CpG DNA. J. Immunol. 172, 954–963 (2004).
  CAS PubMed Google Scholar
• Poeck, H. et al. Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help. Blood 103, 3058–3064 (2004).
  CAS PubMed Google Scholar
• Krieg, A. M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546–549 (1995).
  CAS PubMed Google Scholar
• Chen, W., Kuolee, R. & Yan, H. The potential of 3',5'-cyclic diguanylic acid (c-di-GMP) as an effective vaccine adjuvant. Vaccine 28, 3080–3085 (2010).
  CAS PubMed Google Scholar
• Karaolis, D. K. et al. Bacterial c-di-GMP is an immunostimulatory molecule. J. Immunol. 178, 2171–2181 (2007).
  CAS PubMed Google Scholar
• McWhirter, S. M. et al. A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. J. Exp. Med. 206, 1899–1911 (2009).
  CAS PubMed Central PubMed Google Scholar
• Sauer, J. D. et al. The _N_-ethyl-_N_-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infect. Immun. 79, 688–694 (2011).
  CAS PubMed Google Scholar
• Trinchieri, G. & Sher, A. Cooperation of Toll-like receptor signals in innate immune defence. Nature Rev. Immunol. 7, 179–190 (2007).
  CAS Google Scholar
• Zhu, Q. et al. Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines. Proc. Natl Acad. Sci. USA 105, 16260–16265 (2008).
  CAS PubMed PubMed Central Google Scholar
• Zhu, Q. et al. Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice. J. Clin. Invest. 120, 607–616 (2010).
  CAS PubMed Central PubMed Google Scholar
• Kasturi, S. P. et al. Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470, 543–547 (2011). References 115 and 116 illustrate how combining nucleic acid sensor agonists and optimizing their delivery strategies could allow fine-tuning of the responses to subunit vaccines.
  CAS PubMed Central PubMed Google Scholar
• Remijsen, Q. et al. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ. 18, 581–588 (2011).
  CAS PubMed Central PubMed Google Scholar
• Hashimoto, D., Miller, J. & Merad, M. Dendritic cell and macrophage heterogeneity in vivo. Immunity 35, 323–335 (2011).
  CAS PubMed Central PubMed Google Scholar
• Palucka, K., Banchereau, J. & Mellman, I. Designing vaccines based on biology of human dendritic cell subsets. Immunity 33, 464–478 (2010).
  CAS PubMed Central PubMed Google Scholar
• Gilliet, M., Cao, W. & Liu, Y.-J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nature Rev. Immunol. 8, 594–606 (2008).
  CAS Google Scholar
• Takagi, H. et al. Plasmacytoid dendritic cells are crucial for the initiation of inflammation and T cell immunity in vivo. Immunity 35, 958–971 (2011). This study suggests a direct role of pDCs in the priming of CD8+ T cell responses in vivo.
  CAS PubMed Google Scholar
• Reizis, B., Colonna, M., Trinchieri, G., Barrat, F. & Gilliet, M. Plasmacytoid dendritic cells: one-trick ponies or workhorses of the immune system? Nature Rev. Immunol. 11, 558–565 (2011).
  CAS Google Scholar
• Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54 (Pt 1), 1–13 (1989).
  CAS PubMed Google Scholar
• Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).
  CAS PubMed Google Scholar
• González-Navajas, J. M., Lee, J., David, M. & Raz, E. Immunomodulatory functions of type I interferons. Nature Rev. Immunol. 12, 125–135 (2012).
  Google Scholar
• Sadler, A. J. & Williams, B. R. Interferon-inducible antiviral effectors. Nature Rev. Immunol. 8, 559–568 (2008).
  CAS Google Scholar