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What Have Dendritic Cells Ever Done for Adjuvant Design? Cellular and Molecular Methods for the Rational Development of Vaccine Adjuvants

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Immunomic Discovery of Adjuvants and Candidate Subunit Vaccines

Part of the book series: Immunomics Reviews: ((IMMUN,volume 5))

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Abstract

Our new molecular understanding of immune priming states that dendritic cell (DC) activation is absolutely pivotal for expansion and differentiation of naïve T lymphocytes, and it follows that understanding DC activation is essential to understand and design vaccine adjuvants. This chapter describes how dendritic cells can be used as a core tool to provide detailed quantitative and predictive immunomics information about how adjuvants function. The role of distinct antigen, costimulation, and differentiation signals from activated DC in priming is explained. Four categories of input signals which control DC activation—direct pathogen detection, sensing of injury or cell death, indirect activation via endogenous proinflammatory mediators, and feedback from activated T cells—are compared and contrasted. Practical methods for studying adjuvants using DC are summarized and the importance of DC subset choice, simulating T cell feedback, and use of knockout cells is highlighted. Finally, five case studies are examined that illustrate the benefit of DC activation analysis for understanding vaccine adjuvant function.

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References

  1. Department of Health. (2011). Annual HPV vaccine coverage in England in 2009/2010. Retrieved August 2011, 2011, from http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_123826.pdf.

  2. Didierlaurent AM, Morel S et al (2009) AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol 183(10):6186–6197

    Article  PubMed  CAS  Google Scholar 

  3. Edwards AD, Manickasingham SP et al (2002) Microbial recognition via toll-like receptor-dependent and -independent pathways determines the cytokine response of murine dendritic cell subsets to CD40 triggering. J Immunol 169(7):3652–3660

    PubMed  CAS  Google Scholar 

  4. Rogers NC, Slack EC et al (2005) Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22(4):507–517

    Article  PubMed  CAS  Google Scholar 

  5. LeibundGut-Landmann S, Gross O et al (2007) Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol 8(6):630–638

    Article  PubMed  CAS  Google Scholar 

  6. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392(6673):245–252

    Article  PubMed  CAS  Google Scholar 

  7. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820

    Article  PubMed  CAS  Google Scholar 

  8. Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8(4):279–289

    Article  PubMed  CAS  Google Scholar 

  9. Guermonprez P, Valladeau J et al (2002) Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 20:621–667

    Article  PubMed  CAS  Google Scholar 

  10. Heath WR, Belz GT et al (2004) Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens. Immunol Rev 199:9–26

    Article  PubMed  CAS  Google Scholar 

  11. Reis e Sousa C (2006) Dendritic cells in a mature age. Nat Rev Immunol 6(6):476–483

    Article  PubMed  CAS  Google Scholar 

  12. Sporri R, Reis e Sousa C (2002) Self peptide/MHC class I complexes have a negligible effect on the response of some CD8+ T cells to foreign antigen. Eur J Immunol 32(11):3161–3170

    Article  PubMed  CAS  Google Scholar 

  13. Kapsenberg ML (2003) Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3(12):984–993

    Article  PubMed  CAS  Google Scholar 

  14. Pulendran B, Tang H et al (2008) Division of labor, plasticity, and crosstalk between dendritic cell subsets. Curr Opin Immunol 20(1):61–67

    Article  PubMed  CAS  Google Scholar 

  15. Beutler BA (2009) TLRs and innate immunity. Blood 113(7):1399–1407

    Article  PubMed  CAS  Google Scholar 

  16. Poltorak A, He X et al (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282(5396):2085–2088

    Article  PubMed  CAS  Google Scholar 

  17. De Smedt T, Pajak B et al (1996) Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J Exp Med 184(4):1413–1424

    Article  PubMed  Google Scholar 

  18. Sparwasser T, Koch E-S et al (1998) Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 28(6):2045–2054

    Article  PubMed  CAS  Google Scholar 

  19. Schnurr M, Then F et al (2000) Extracellular ATP and TNF-α synergize in the activation and maturation of human dendritic cells. J Immunol 165(8):4704–4709

    PubMed  CAS  Google Scholar 

  20. MacAry PA, Javid B et al (2004) HSP70 peptide binding mutants separate antigen delivery from dendritic cell stimulation. Immunity 20(1):95–106

    Article  PubMed  CAS  Google Scholar 

  21. Sancho D, Joffre OP et al (2009) Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458(7240):899–903

    Article  PubMed  CAS  Google Scholar 

  22. Randolph GJ, Ochando J et al (2008) Migration of dendritic cell subsets and their precursors. Annu Rev Immunol 26(1):293–316

    Article  PubMed  CAS  Google Scholar 

  23. Niessen F, Schaffner F et al (2008) Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 452(7187):654–658

    Article  PubMed  CAS  Google Scholar 

  24. Snijders A, Kalinski P et al (1998) High-level IL-12 production by human dendritic cells requires two signals. Int Immunol 10(11):1593–1598

    Article  PubMed  CAS  Google Scholar 

  25. Schulz O, Edwards AD et al (2000) CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 13(4):453–462

    Article  PubMed  CAS  Google Scholar 

  26. Sharpe AH (2009) Mechanisms of costimulation. Immunol Rev 229(1):5–11

    Article  PubMed  CAS  Google Scholar 

  27. Wu CC, Hayashi T et al (2007) Immunotherapeutic activity of a conjugate of a Toll-like receptor 7 ligand. Proc Natl Acad Sci USA 104(10):3990–3995

    Article  PubMed  CAS  Google Scholar 

  28. Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3(2):133–146

    Article  PubMed  CAS  Google Scholar 

  29. Korn T, Bettelli E et al (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517

    Article  PubMed  CAS  Google Scholar 

  30. Edwards AD, Diebold SS et al (2003) Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8 alpha(+) DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol 33(4):827–833

    Article  PubMed  CAS  Google Scholar 

  31. Amsen D, Blander JM et al (2004) Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117(4):515–526

    Article  PubMed  CAS  Google Scholar 

  32. Porgador A, Yewdell JW et al (1997) Localization, quantitation, and in situ detection of specific peptide-MHC class I complexes using a monoclonal antibody. Immunity 6(6):715–726

    Article  PubMed  CAS  Google Scholar 

  33. Zhong G, Sousa CRe et al (1997) Production, specificity, and functionality of monoclonal antibodies to specific peptide–major histocompatibility complex class II complexes formed by processing of exogenous protein. Proc Natl Acad Sci USA 94(25):13856–13861

    Article  PubMed  CAS  Google Scholar 

  34. Amigorena S, Savina A (2010) Intracellular mechanisms of antigen cross presentation in dendritic cells. Curr Opin Immunol 22(1):109–117

    Article  PubMed  CAS  Google Scholar 

  35. Haswell LE, Glennie MJ et al (2001) Analysis of the oligomeric requirement for signaling by CD40 using soluble multimeric forms of its ligand, CD154. Eur J Immunol 31(10):3094–3100

    Article  PubMed  CAS  Google Scholar 

  36. Edwards AD, Chaussabel D et al (2003) Relationships among murine CD11c(high) dendritic cell subsets as revealed by baseline gene expression patterns. J Immunol 171(1):47–60

    PubMed  CAS  Google Scholar 

  37. Giudice EL, Campbell JD (2006) Needle-free vaccine delivery. Adv Drug Deliv Rev 58(1):68–89

    Article  PubMed  CAS  Google Scholar 

  38. Brawand P, Fitzpatrick DR et al (2002) Murine plasmacytoid pre-dendritic cells generated from Flt3 ligand-supplemented bone marrow cultures are immature APCs. J Immunol 169(12):6711–6719

    PubMed  CAS  Google Scholar 

  39. Inaba K, Inaba M et al (1992) Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 176(6):1693–1702

    Article  PubMed  CAS  Google Scholar 

  40. Romani N, Gruner S et al (1994) Proliferating dendritic cell progenitors in human blood. J Exp Med 180(1):83–93

    Article  PubMed  CAS  Google Scholar 

  41. Girolomoni G, Lutz MB et al (1995) Establishment of a cell line with features of early dendritic cell precursors from fetal mouse skin. Eur J Immunol 25(8):2163–2169

    Article  PubMed  CAS  Google Scholar 

  42. Fairchild PJ, Brook FA et al (2000) Directed differentiation of dendritic cells from mouse embryonic stem cells. Curr Biol 10(23):1515–1518

    Article  PubMed  CAS  Google Scholar 

  43. Bogunovic M, Ginhoux F et al (2006) Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men. J Exp Med 203(12):2627–2638

    Article  PubMed  CAS  Google Scholar 

  44. Hornung V, Guenthner-Biller M et al (2005) Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 11(3):263–270

    Article  PubMed  CAS  Google Scholar 

  45. Pichlmair A, Diebold SS et al (2007) Tubulovesicular structures within vesicular stomatitis virus G protein-pseudotyped lentiviral vector preparations carry DNA and stimulate antiviral responses via Toll-like receptor 9. J Virol 81(2):539–547

    Article  PubMed  CAS  Google Scholar 

  46. Sousa CRe, Hieny S et al (1997) In vivo microbial stimulation induces rapid CD40 ligand–independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J Exp Med 186(11):1819–1829

    Article  Google Scholar 

  47. Underhill DM, Ozinsky A et al (1999) The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401(6755):811–815

    Article  PubMed  CAS  Google Scholar 

  48. Diebold SS, Kaisho T et al (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303(5663):1529–1531

    Article  PubMed  CAS  Google Scholar 

  49. Delaloye J, Roger T et al (2009) Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. PLoS Pathog 5(6):e1000480

    Article  PubMed  Google Scholar 

  50. Martinez J, Huang X et al (2010) Toll-like receptor 8-mediated activation of murine plasmacytoid dendritic cells by vaccinia viral DNA. Proc Natl Acad Sci USA 107(14):6442–6447

    Article  PubMed  CAS  Google Scholar 

  51. Geeraedts F, Goutagny N et al (2008) Superior immunogenicity of inactivated whole virus H5N1 influenza vaccine is primarily controlled by Toll-like receptor signalling. PLoS Pathog 4(8):e1000138

    Article  PubMed  Google Scholar 

  52. Fransen F, Stenger RM et al (2010) Differential effect of TLR2 and TLR4 on the immune response after immunization with a vaccine against Neisseria meningitidis or Bordetella pertussis. PLoS One 5(12):e15692

    Article  PubMed  CAS  Google Scholar 

  53. Gavin AL, Hoebe K et al (2006) Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314(5807):1936–1938

    Article  PubMed  CAS  Google Scholar 

  54. De Gregorio E, D’Oro U et al (2009) Immunology of TLR-independent vaccine adjuvants. Curr Opin Immunol 21(3):339–345

    Article  PubMed  Google Scholar 

  55. Einstein MH, Baron M et al (2009) Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18–45 years. Hum Vaccin 5(10):705–719

    Article  PubMed  CAS  Google Scholar 

  56. Qureshi N, Takayama K et al (1982) Purification and structural determination of nontoxic lipid A obtained from the lipopolysaccharide of Salmonella typhimurium. J Biol Chem 257(19):11808–11815

    PubMed  CAS  Google Scholar 

  57. Brown GD, Gordon S (2001) Immune recognition: a new receptor for [beta]-glucans. Nature 413(6851):36–37

    Article  PubMed  CAS  Google Scholar 

  58. Werninghaus K, Babiak A et al (2009) Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRgamma-Syk-Card9-dependent innate immune activation. J Exp Med 206(1):89–97

    Article  PubMed  CAS  Google Scholar 

  59. Heit A, Maurer T et al (2003) Cutting edge: Toll-like receptor 9 expression is not required for CpG DNA-aided cross-presentation of DNA-conjugated antigens but essential for cross-priming of CD8 T cells. J Immunol 170(6):2802–2805

    PubMed  CAS  Google Scholar 

  60. Oh JZ, Kedl RM (2010) The capacity to induce cross-presentation dictates the success of a TLR7 agonist-conjugate vaccine for eliciting cellular immunity. J Immunol 185(8):4602–4608

    Article  PubMed  CAS  Google Scholar 

  61. Schlosser E, Mueller M et al (2008) TLR ligands and antigen need to be coencapsulated into the same biodegradable microsphere for the generation of potent cytotoxic T lymphocyte responses. Vaccine 26(13):1626–1637

    Article  PubMed  CAS  Google Scholar 

  62. Sharp FA, Ruane D et al (2009) Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. Proc Natl Acad Sci 106(3):870–875

    Article  PubMed  CAS  Google Scholar 

  63. Henriksen-Lacey M, Christensen D et al (2010) Liposomal cationic charge and antigen adsorption are important properties for the efficient deposition of antigen at the injection site and ability of the vaccine to induce a CMI response. J Control Release 145(2):102–108

    Article  PubMed  CAS  Google Scholar 

  64. Dempsey PW, Allison ME et al (1996) C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271(5247):348–350

    Article  PubMed  CAS  Google Scholar 

  65. Nohria A, Rubin RH (1994) Cytokines as potential vaccine adjuvants. Biotherapy 7(3):261–269

    Article  PubMed  CAS  Google Scholar 

  66. Sporri R, Reis e Sousa C (2005) Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function. Nat Immunol 6(2):163–170

    Article  PubMed  Google Scholar 

  67. Kool M, Soullié T et al (2008) Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med 205(4):869–882

    Article  PubMed  CAS  Google Scholar 

  68. Eisenbarth SC, Colegio OR et al (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453(7198):1122–1126

    Article  PubMed  CAS  Google Scholar 

  69. Kool M, Pétrilli V et al (2008) Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol 181(6):3755–3759

    PubMed  CAS  Google Scholar 

  70. Jordan MB, Mills DM et al (2004) Promotion of B cell immune responses via an alum-induced myeloid cell population. Science 304(5678):1808–1810

    Article  PubMed  CAS  Google Scholar 

  71. Bennett SR, Carbone FR et al (1998) Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393(6684):478–480

    Article  PubMed  CAS  Google Scholar 

  72. Ridge JP, Di Rosa F et al (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393(6684):474–478

    Article  PubMed  CAS  Google Scholar 

  73. Schoenberger SP, Toes RE et al (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393(6684):480–483

    Article  PubMed  CAS  Google Scholar 

  74. Diehl L, den Boer AT et al (1999) CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med 5(7):774–779

    Article  PubMed  CAS  Google Scholar 

  75. Ahonen CL, Doxsee CL et al (2004) Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN. J Exp Med 199(6):775–784

    Article  PubMed  CAS  Google Scholar 

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Disclaimer

The effectiveness of your adjuvant can go down as well as up. The complexity of both the innate and adaptive immune systems should never be underestimated. In this chapter, one antigen presenting cell, three T cell priming signals, and four input signals are discussed. Although DCs take a central role in controlling immune priming and polarization, other cell types have an equally important role in both sensing antigen and controlling immunity. Similarly, classification of DC–T cell signals into three categories is helpful; however, in reality, the interaction between these cells is so complex that it is termed the immune synapse, and many signals fall into more than one category. Although signal 3 is conceptually vital, and study of cytokines in this class such as IL-12 has proven highly informative, much is still unknown about what signals lead to which immune responses. Worse, for many important pathogens, the class of immunity required for protection is still unclear. DC studies are only a simple starting point and all adjuvants must ultimately be tested in vivo to determine efficacy.

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  1. Reading School of Pharmacy, Chemistry & Pharmacy, Whiteknights, Reading, UK

    Alexander D. Edwards

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  1. Alexander D. Edwards
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Correspondence to Alexander D. Edwards .

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  1. Aston Pharmacy School, School of Life and Health Sciences, University of Aston, Aston Triangle, Birmingham, B4 7ET, United Kingdom

    Darren R. Flower

  2. Aston Pharmacy School, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, United Kingdom

    Yvonne Perrie

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Edwards, A.D. (2013). What Have Dendritic Cells Ever Done for Adjuvant Design? Cellular and Molecular Methods for the Rational Development of Vaccine Adjuvants. In: Flower, D., Perrie, Y. (eds) Immunomic Discovery of Adjuvants and Candidate Subunit Vaccines. Immunomics Reviews:, vol 5. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5070-2_8

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