Human plasmacytoid dendritic cells (PDCs) can produce interferon (IFN)-α and/or mature and participate in the adaptive immune response. Three classes of CpG oligonucleotide ligands for Toll-like receptor (TLR)9 can be distinguished by different sequence motifs and different abilities to stimulate IFN-α production and maturation of PDCs. We show that the nature of the PDC response is determined by the higher order structure and endosomal location of the CpG oligonucleotide. Activation of TLR9 by the multimeric CpG-A occurs in transferrin receptor (TfR)-positive endosomes and leads exclusively to IFN-α production, whereas monomeric CpG-B oligonucleotides localize to lysosome-associated membrane protein (LAMP)-1–positive endosomes and promote maturation of PDCs. However, CpG-B, when complexed into microparticles, localizes in TfR-positive endosomes and induces IFN-α from PDCs, whereas monomeric forms of CpG-A localize to LAMP-1–positive endosomes accompanied by the loss of IFN-α production and a gain in PDC maturation activity. CpG-C sequences, which induce both IFN-α and maturation of PDCs, are distributed in both type of endosomes. Encapsulation of CpG-C in liposomes stable above pH 5.75 completely abrogated the IFN-α response while increasing PDC maturation. This establishes that the primary determinant of TLR9 signaling is not valency but endosomal location and demonstrates a strict compartmentalization of the biological response to TLR9 activation in PDCs.
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7 August 2006
Article|
July 24 2006
Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation
Cristiana Guiducci,
Cristiana Guiducci
1Dynavax Technologies Corporation, Berkeley, CA 94710
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Gary Ott,
Gary Ott
1Dynavax Technologies Corporation, Berkeley, CA 94710
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Jean H. Chan,
Jean H. Chan
1Dynavax Technologies Corporation, Berkeley, CA 94710
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Emily Damon,
Emily Damon
1Dynavax Technologies Corporation, Berkeley, CA 94710
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Carlo Calacsan,
Carlo Calacsan
1Dynavax Technologies Corporation, Berkeley, CA 94710
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Tracy Matray,
Tracy Matray
1Dynavax Technologies Corporation, Berkeley, CA 94710
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Kyung-Dall Lee,
Kyung-Dall Lee
2Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109
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Robert L. Coffman,
Robert L. Coffman
1Dynavax Technologies Corporation, Berkeley, CA 94710
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Franck J. Barrat
Franck J. Barrat
1Dynavax Technologies Corporation, Berkeley, CA 94710
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Cristiana Guiducci
1Dynavax Technologies Corporation, Berkeley, CA 94710
Gary Ott
1Dynavax Technologies Corporation, Berkeley, CA 94710
Jean H. Chan
1Dynavax Technologies Corporation, Berkeley, CA 94710
Emily Damon
1Dynavax Technologies Corporation, Berkeley, CA 94710
Carlo Calacsan
1Dynavax Technologies Corporation, Berkeley, CA 94710
Tracy Matray
1Dynavax Technologies Corporation, Berkeley, CA 94710
Kyung-Dall Lee
2Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109
Robert L. Coffman
1Dynavax Technologies Corporation, Berkeley, CA 94710
Franck J. Barrat
1Dynavax Technologies Corporation, Berkeley, CA 94710
CORRESPONDENCE Franck J. Barrat: [email protected]
Abbreviations used: cDC, conventional DC; ISS, immunostimulatory oligonucleotide sequences; LAMP, lysosome-associated membrane protein; ODN, oligodeoxynucleotide; PDC, plasmacytoid DC; ss, single strand; TfR, transferrin receptor; TLR, Toll-like receptor.
Received:
February 21 2006
Accepted:
June 29 2006
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2006
J Exp Med (2006) 203 (8): 1999–2008.
Article history
Received:
February 21 2006
Accepted:
June 29 2006
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Citation
Cristiana Guiducci, Gary Ott, Jean H. Chan, Emily Damon, Carlo Calacsan, Tracy Matray, Kyung-Dall Lee, Robert L. Coffman, Franck J. Barrat; Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation . J Exp Med 7 August 2006; 203 (8): 1999–2008. doi: https://doi.org/10.1084/jem.20060401
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