The Journal of Experimental Medicine
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Published online 6 February 2006 doi:10.1084/jem.20051720
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 2, 413-424
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ARTICLE

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

Troy Querec1, Soumaya Bennouna1, Sefik Alkan3, Yasmina Laouar4, Keith Gorden3, Richard Flavell4, Shizuo Akira5, Rafi Ahmed1, and Bali Pulendran1,2

1 Emory Vaccine Center and 2 Department of Pathology, Emory University, Atlanta, GA 30329
3 3M Pharmaceuticals, St. Paul, MN 55144
4 Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
5 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan

CORRESPONDENCE Bali Pulendran: bpulend{at}rmy.emory.edu

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.

Abbreviations used: mDC, monocyte-derived DC; MOI, multiplicity of infection; pDC, plasmacytoid DC; PRR, pathogen recognition receptor; TLR, Toll-like receptor; YF-17D, yellow fever vaccine 17D.


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