Home LiteratureArticle Details
PMID: 16461338 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity.

The Journal of experimental medicine ·Vol. 203 ·No. 2 ·2006-02-20 ·Pages 413-24

Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, Flavell R, Akira S, Ahmed R, Pulendran B

Abstract

The live attenuated yellow fever vaccine 17D (YF-17D) is one of the most effective vaccines available, with a 65-yr history of use in >400 million people globally. Despite this efficacy, there is presently no information about the immunological mechanisms by which YF-17D acts. Here, we present data that suggest that YF-17D activates multiple Toll-like receptors (TLRs) on dendritic cells (DCs) to elicit a broad spectrum of innate and adaptive immune responses. Specifically, YF-17D activates multiple DC subsets via TLRs 2, 7, 8, and 9 to elicit the proinflammatory cytokines interleukin (IL)-12p40, IL-6, and interferon-alpha. Interestingly, the resulting adaptive immune responses are characterized by a mixed T helper cell (Th)1/Th2 cytokine profile and antigen-specific CD8+ T cells. Furthermore, distinct TLRs appear to differentially control the Th1/Th2 balance; thus, whilst MyD88-deficient mice show a profound impairment of Th1 cytokines, TLR2-deficient mice show greatly enhanced Th1 and Tc1 responses to YF-17D. Together, these data enhance our understanding of the molecular mechanism of action of YF-17D, and highlight the potential of vaccination strategies that use combinations of different TLR ligands to stimulate polyvalent immune responses.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics,physiology Amino Acid Sequence Animals Cell Line Cells, Cultured Dendritic Cells/immunology,metabolism Humans Immunity, Active Membrane Glycoproteins/genetics,physiology Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Molecular Sequence Data Myeloid Differentiation Factor 88 Receptors, Interleukin-1/genetics,physiology Th1 Cells/immunology,metabolism Th2 Cells/immunology,metabolism Toll-Like Receptor 2/physiology Toll-Like Receptor 7/physiology Toll-Like Receptor 8/physiology Toll-Like Receptor 9/physiology Toll-Like Receptors/physiology Vaccines, Attenuated/immunology Yellow Fever Vaccine/immunology
Chemicals
Adaptor Proteins, Signal Transducing MYD88 protein, human Membrane Glycoproteins Myd88 protein, mouse Myeloid Differentiation Factor 88 Receptors, Interleukin-1 TIRAP protein, human TIRAP protein, mouse Toll-Like Receptor 2 Toll-Like Receptor 7 Toll-Like Receptor 8 Toll-Like Receptor 9 Toll-Like Receptors Vaccines, Attenuated Yellow Fever Vaccine
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Querec Troy
Emory Vaccine Center, Emory University, Atlanta, GA 30329, USA.
Bennouna Soumaya
Alkan Sefik
Laouar Yasmina
Gorden Keith
Flavell Richard
Akira Shizuo
Ahmed Rafi
Pulendran Bali
References (79)
79 references, click to expand
  1. Toll-like receptors control activation of adaptive immune responses.
    Nat Immunol. 2001 Oct;2(10):947-50 PMID: 11547333
  2. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus.
    J Biol Chem. 2005 Feb 18;280(7):5571-80 PMID: 15579900
  3. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells.
    J Biol Chem. 2001 Oct 5;276(40):37692-9 PMID: 11477091
  4. ChimeriVax-West Nile virus live-attenuated vaccine: preclinical evaluation of safety, immunogenicity, and efficacy.
    J Virol. 2004 Nov;78(22):12497-507 PMID: 15507637
  5. 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. 2003 Mar 15;170(6):2802-5 PMID: 12626528
  6. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.
    Science. 1998 Dec 11;282(5396):2085-8 PMID: 9851930
  7. Yellow fever 17D as a vaccine vector for microbial CTL epitopes: protection in a rodent malaria model.
    J Exp Med. 2005 Jan 17;201(2):201-9 PMID: 15657290
  8. Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation.
    Gastroenterology. 2004 Nov;127(5):1513-24 PMID: 15521019
  9. Toll-like receptors.
    Annu Rev Immunol. 2003;21:335-76 PMID: 12524386
  10. Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): phase 2 clinical trials for safety and immunogenicity, effect of vaccine dose and schedule, and memory response to challenge with inactivated Japanese encephalitis antigen.
    J Infect Dis. 2003 Oct 15;188(8):1213-30 PMID: 14551893
  11. Identification and characterization of avian retroviruses in chicken embryo-derived yellow fever vaccines: investigation of transmission to vaccine recipients.
    J Virol. 2003 Jan;77(2):1105-11 PMID: 12502826
  12. Signaling by toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages.
    Infect Immun. 2001 Mar;69(3):1477-82 PMID: 11179315
  13. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8.
    J Immunol. 2005 Feb 1;174(3):1259-68 PMID: 15661881
  14. Construction of yellow fever/St. Louis encephalitis chimeric virus and the use of chimeras as a diagnostic tool.
    Am J Trop Med Hyg. 2004 Nov;71(5):639-45 PMID: 15569798
  15. Growth characteristics of the chimeric Japanese encephalitis virus vaccine candidate, ChimeriVax-JE (YF/JE SA14--14--2), in Culex tritaeniorhynchus, Aedes albopictus, and Aedes aegypti mosquitoes.
    Am J Trop Med Hyg. 2000 Apr;62(4):480-4 PMID: 11220763
  16. Recombinant yellow fever viruses are effective therapeutic vaccines for treatment of murine experimental solid tumors and pulmonary metastases.
    J Virol. 2000 Oct;74(19):9197-205 PMID: 10982366
  17. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.
    Science. 2004 Mar 5;303(5663):1526-9 PMID: 14976262
  18. Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism.
    Nat Immunol. 2001 Apr;2(4):346-52 PMID: 11276206
  19. Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo.
    J Immunol. 2001 Nov 1;167(9):5067-76 PMID: 11673516
  20. Variegation of the immune response with dendritic cells and pathogen recognition receptors.
    J Immunol. 2005 Mar 1;174(5):2457-65 PMID: 15728447
  21. Recognition of single-stranded RNA viruses by Toll-like receptor 7.
    Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5598-603 PMID: 15034168
  22. TLR2 and TLR4 stimulation differentially induce cytokine secretion in human neonatal, adult, and murine mononuclear cells.
    J Interferon Cytokine Res. 2004 Sep;24(9):543-52 PMID: 15450130
  23. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling.
    Nature. 2003 Aug 14;424(6950):743-8 PMID: 12872135
  24. Regulatory role of Toll-like receptor 2 during infection with Trypanosoma cruzi.
    J Endotoxin Res. 2004;10(6):425-30 PMID: 15588426
  25. Persistence of neutralizing antibody 30-35 years after immunization with 17D yellow fever vaccine.
    Bull World Health Organ. 1981;59(6):895-900 PMID: 6978196
  26. An innately interesting decade of research in immunology.
    Nat Med. 2004 Dec;10(12):1307-20 PMID: 15580257
  27. Plasmacytoid dendritic cell precursors/type I interferon-producing cells sense viral infection by Toll-like receptor (TLR) 7 and TLR9.
    Springer Semin Immunopathol. 2005 Jan;26(3):221-9 PMID: 15592841
  28. Human cardiac inflammatory responses triggered by Coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent.
    Cell Microbiol. 2005 Aug;7(8):1117-26 PMID: 16008579
  29. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells.
    J Exp Med. 2003 Aug 4;198(3):513-20 PMID: 12900525
  30. Cutting edge: Role of Toll-like receptor 9 in CpG DNA-induced activation of human cells.
    J Immunol. 2001 Oct 1;167(7):3555-8 PMID: 11564765
  31. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens.
    Nature. 1999 Oct 21;401(6755):811-5 PMID: 10548109
  32. Immunogenicity, genetic stability, and protective efficacy of a recombinant, chimeric yellow fever-Japanese encephalitis virus (ChimeriVax-JE) as a live, attenuated vaccine candidate against Japanese encephalitis.
    Virology. 1999 May 10;257(2):363-72 PMID: 10329547
  33. Safety and efficacy of chimeric yellow Fever-dengue virus tetravalent vaccine formulations in nonhuman primates.
    J Virol. 2004 May;78(9):4761-75 PMID: 15078958
  34. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4.
    Nature. 2002 Nov 21;420(6913):324-9 PMID: 12447441
  35. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function.
    Immunity. 2004 Jul;21(1):107-19 PMID: 15345224
  36. Immune activation: death, danger and dendritic cells.
    Curr Biol. 2004 Jan 6;14(1):R30-2 PMID: 14711433
  37. Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos.
    J Immunol. 2003 Nov 15;171(10):4984-9 PMID: 14607893
  38. Yersinia V-antigen exploits toll-like receptor 2 and CD14 for interleukin 10-mediated immunosuppression.
    J Exp Med. 2002 Oct 21;196(8):1017-24 PMID: 12391013
  39. IL-10 released by concomitant TLR2 stimulation blocks the induction of a subset of Th1 cytokines that are specifically induced by TLR4 or TLR3 in human dendritic cells.
    J Immunol. 2004 Dec 15;173(12):7548-55 PMID: 15585882
  40. CpG motifs in bacterial DNA and their immune effects.
    Annu Rev Immunol. 2002;20:709-60 PMID: 11861616
  41. THE EFFECT OF PROLONGED CULTIVATION IN VITRO UPON THE PATHOGENICITY OF YELLOW FEVER VIRUS.
    J Exp Med. 1937 May 31;65(6):767-86 PMID: 19870633
  42. A subset of Toll-like receptor ligands induces cross-presentation by bone marrow-derived dendritic cells.
    J Immunol. 2003 Apr 15;170(8):4102-10 PMID: 12682240
  43. TIRAP: an adapter molecule in the Toll signaling pathway.
    Nat Immunol. 2001 Sep;2(9):835-41 PMID: 11526399
  44. THE USE OF YELLOW FEVER VIRUS MODIFIED BY IN VITRO CULTIVATION FOR HUMAN IMMUNIZATION.
    J Exp Med. 1937 May 31;65(6):787-800 PMID: 19870634
  45. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin.
    J Exp Med. 2005 Jan 3;201(1):19-25 PMID: 15630134
  46. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components.
    Immunity. 1999 Oct;11(4):443-51 PMID: 10549626
  47. TLR8 and TLR7 are involved in the host's immune response to human parechovirus 1.
    Eur J Immunol. 2005 Aug;35(8):2416-23 PMID: 16025564
  48. Yellow fever virus replicons as an expression system for hepatitis C virus structural proteins.
    J Virol. 2003 Jan;77(2):1644-8 PMID: 12502883
  49. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.
    Science. 2003 Aug 1;301(5633):640-3 PMID: 12855817
  50. Pathogen recognition with Toll-like receptors.
    Curr Opin Immunol. 2005 Aug;17(4):338-44 PMID: 15950447
  51. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.
    Science. 2004 Mar 5;303(5663):1529-31 PMID: 14976261
  52. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.
    Nature. 2001 Oct 18;413(6857):732-8 PMID: 11607032
  53. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells.
    J Immunol. 2004 Apr 15;172(8):4733-43 PMID: 15067049
  54. Tolerance, danger, and the extended family.
    Annu Rev Immunol. 1994;12:991-1045 PMID: 8011301
  55. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction.
    Nat Immunol. 2003 Feb;4(2):161-7 PMID: 12539043
  56. 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 U S A. 2005 Oct 18;102(42):15190-4 PMID: 16219698
  57. Cell activation by synthetic lipopeptides of the hepatitis C virus (HCV)--core protein is mediated by toll like receptors (TLRs) 2 and 4.
    Immunol Lett. 2002 Nov 1;84(2):89-95 PMID: 12270544
  58. Assessment of IgG antibodies against yellow fever virus after vaccination with 17D by different assays: neutralization test, haemagglutination inhibition test, immunofluorescence assay and ELISA.
    Trop Med Int Health. 1999 Dec;4(12):867-71 PMID: 10632996
  59. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF.
    J Exp Med. 2003 Oct 6;198(7):1043-55 PMID: 14517278
  60. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling.
    J Immunol. 2002 Dec 15;169(12):6668-72 PMID: 12471095
  61. Yellow fever virus 17D envelope and NS3 proteins are major targets of the antiviral T cell response in mice.
    Virology. 2002 Apr 25;296(1):117-24 PMID: 12036323
  62. Inferences, questions and possibilities in Toll-like receptor signalling.
    Nature. 2004 Jul 8;430(6996):257-63 PMID: 15241424
  63. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection.
    Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3516-21 PMID: 14993594
  64. Human cytotoxic T lymphocyte responses to live attenuated 17D yellow fever vaccine: identification of HLA-B35-restricted CTL epitopes on nonstructural proteins NS1, NS2b, NS3, and the structural protein E.
    Virology. 2002 Feb 1;293(1):151-63 PMID: 11853408
  65. Cell type-specific involvement of RIG-I in antiviral response.
    Immunity. 2005 Jul;23(1):19-28 PMID: 16039576
  66. Porphyromonas gingivalis 67-kDa fimbriae induced cytokine production and osteoclast differentiation utilizing TLR2.
    FEMS Microbiol Lett. 2003 Dec 5;229(1):49-55 PMID: 14659542
  67. Toll-like receptor control of the adaptive immune responses.
    Nat Immunol. 2004 Oct;5(10):987-95 PMID: 15454922
  68. Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma.
    J Immunol. 2004 Mar 1;172(5):2739-43 PMID: 14978071
  69. Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling.
    J Virol. 2002 Sep;76(17):8729-36 PMID: 12163593
  70. Construction, safety, and immunogenicity in nonhuman primates of a chimeric yellow fever-dengue virus tetravalent vaccine.
    J Virol. 2001 Aug;75(16):7290-304 PMID: 11462001
  71. Live attenuated yellow fever 17D infects human DCs and allows for presentation of endogenous and recombinant T cell epitopes.
    J Exp Med. 2005 Nov 7;202(9):1179-84 PMID: 16260489
  72. The expression of toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells.
    Arthritis Rheum. 2005 Aug;52(8):2313-22 PMID: 16052591
  73. Approaching the asymptote? Evolution and revolution in immunology.
    Cold Spring Harb Symp Quant Biol. 1989;54 Pt 1:1-13 PMID: 2700931
  74. Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells.
    Eur J Immunol. 2004 Mar;34(3):796-805 PMID: 14991609
  75. Mouse and human dendritic cell subtypes.
    Nat Rev Immunol. 2002 Mar;2(3):151-61 PMID: 11913066
  76. MyD88 is critical for the development of innate and adaptive immunity during acute lymphocytic choriomeningitis virus infection.
    Eur J Immunol. 2005 Mar;35(3):822-30 PMID: 15724245
  77. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells.
    Nat Immunol. 2005 Aug;6(8):769-76 PMID: 15995707
  78. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells.
    J Immunol. 2004 Mar 15;172(6):3712-8 PMID: 15004175
  79. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors.
    Science. 1999 Jul 30;285(5428):732-6 PMID: 10426995
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20051720
Published
2006-02-20
Epub
2006-00-06
Pages
413-24
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2118210
Subset
IM
Grants
NIAID NIH HHS · U19 AI057266 · United States
NIDDK NIH HHS · R01 DK057665 · United States
NIAID NIH HHS · R01 AI056499 · United States
NIAID NIH HHS · R21 AI056957 · United States
NIAID NIH HHS · R01 AI048638 · United States
NIAID NIH HHS · U54 AI057157 · United States
External Links
PubMed source DOI: 10.1084/jem.20051720 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2