Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity.
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.
Querec
Troy
T
Emory Vaccine Center, Emory University, Atlanta, GA 30329, USA.
Bennouna
Soumaya
S
Alkan
Sefik
S
Laouar
Yasmina
Y
Gorden
Keith
K
Flavell
Richard
R
Akira
Shizuo
S
Ahmed
Rafi
R
Pulendran
Bali
B
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007110:Immunity, Active; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000502:physiology; D051200:Toll-Like Receptor 8 / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*; D014613:Vaccines, Attenuated / Q000276:immunology; D022341:Yellow Fever Vaccine / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C499045:TIRAP protein, mouse; D051195:Toll-Like Receptor 2; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014613:Vaccines, Attenuated; D022341:Yellow Fever Vaccine