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Science 298 (5595): 1025-1029

Copyright © 2002 by the American Association for the Advancement of Science

Toll-Like Receptor 4-Dependent Activation of Dendritic Cells by beta -Defensin 2 

Arya Biragyn,1* Pier Adelchi Ruffini,1dagger Cynthia A. Leifer,2 Elena Klyushnenkova,3 Alexander Shakhov,3 Oleg Chertov,4 Aiko K. Shirakawa,5 Joshua M. Farber,5 David M. Segal,2 Joost J. Oppenheim,6 Larry W. Kwak1

beta -Defensins are small antimicrobial peptides of the innate immune system produced in response to microbial infection of mucosal tissue and skin. We demonstrate that murine beta -defensin 2 (mDF2beta ) acts directly on immature dendritic cells as an endogenous ligand for Toll-like receptor 4 (TLR-4), inducing up-regulation of costimulatory molecules and dendritic cell maturation. These events, in turn, trigger robust, type 1 polarized adaptive immune responses in vivo, suggesting that mDF2beta may play an important role in immunosurveillance against pathogens and, possibly, self antigens or tumor antigens.

1 Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
2 Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892-1360, USA.
3 Intramural Research Support Program and
4 Protein Chemistry Laboratory, Science Applications International Corporation, Frederick, MD 21702, USA.
5 Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
6 Laboratory of Molecular Immunoregulation, NCI, Frederick, MD 21702, USA.
*   To whom correspondence should be addressed. E-mail: arya{at}

dagger    On leave of absence from Divisione di Oncologia Medica Falck, Ospedale Niguarda Ca Granda, Milan, Italy.

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Why Is the Arg5-Glu13 Salt Bridge Conserved in Mammalian {alpha}-Defensins?.
Z. Wu, X. Li, E. de Leeuw, B. Ericksen, and W. Lu (2005)
J. Biol. Chem. 280, 43039-43047
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Human {beta}-Defensins Suppress Human Immunodeficiency Virus Infection: Potential Role in Mucosal Protection.
L. Sun, C. M. Finnegan, T. Kish-Catalone, R. Blumenthal, P. Garzino-Demo, G. M. La Terra Maggiore, S. Berrone, C. Kleinman, Z. Wu, S. Abdelwahab, et al. (2005)
J. Virol. 79, 14318-14329
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Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus.
F. J. Barrat, T. Meeker, J. Gregorio, J. H. Chan, S. Uematsu, S. Akira, B. Chang, O. Duramad, and R. L. Coffman (2005)
J. Exp. Med. 202, 1131-1139
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Reconstruction of the Conserved {beta}-Bulge in Mammalian Defensins Using D-Amino Acids.
C. Xie, A. Prahl, B. Ericksen, Z. Wu, P. Zeng, X. Li, W.-Y. Lu, J. Lubkowski, and W. Lu (2005)
J. Biol. Chem. 280, 32921-32929
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Cationic Antimicrobial Peptide Resistance in Neisseria meningitidis.
Y.-L. Tzeng, K. D. Ambrose, S. Zughaier, X. Zhou, Y. K. Miller, W. M. Shafer, and D. S. Stephens (2005)
J. Bacteriol. 187, 5387-5396
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E Cario (2005)
Gut 54, 1182-1193
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Toll-Like Receptors on Tumor Cells Facilitate Evasion of Immune Surveillance.
B. Huang, J. Zhao, H. Li, K.-L. He, Y. Chen, L. Mayer, J. C. Unkeless, and H. Xiong (2005)
Cancer Res. 65, 5009-5014
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Impact of LL-37 on anti-infective immunity.
D. M. E. Bowdish, D. J. Davidson, Y. E. Lau, K. Lee, M. G. Scott, and R. E. W. Hancock (2005)
J. Leukoc. Biol. 77, 451-459
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Defensin deficiency, intestinal microbes, and the clinical phenotypes of Crohn's disease.
J. Wehkamp, M. Schmid, K. Fellermann, and E. F. Stange (2005)
J. Leukoc. Biol. 77, 460-465
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Thematic review series: The Immune System and Atherogenesis. Paying the price for pathogen protection: toll receptors in atherogenesis.
P. Tobias and L. K. Curtiss (2005)
J. Lipid Res. 46, 404-411
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Alerting dendritic cells to pathogens: The importance of Toll-like receptor signaling of stromal cells.
M. Colonna (2004)
PNAS 101, 16083-16084
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Human Ribonuclease A Superfamily Members, Eosinophil-Derived Neurotoxin and Pancreatic Ribonuclease, Induce Dendritic Cell Maturation and Activation.
D. Yang, Q. Chen, H. F. Rosenberg, S. M. Rybak, D. L. Newton, Z. Y. Wang, Q. Fu, V. T. Tchernev, M. Wang, B. Schweitzer, et al. (2004)
J. Immunol. 173, 6134-6142
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Antimicrobial proteins and peptides: anti-infective molecules of mammalian leukocytes.
O. Levy (2004)
J. Leukoc. Biol. 76, 909-925
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{beta}-Defensin-2 Expression Is Regulated by TLR Signaling in Intestinal Epithelial Cells.
P. Vora, A. Youdim, L. S. Thomas, M. Fukata, S. Y. Tesfay, K. Lukasek, K. S. Michelsen, A. Wada, T. Hirayama, M. Arditi, et al. (2004)
J. Immunol. 173, 5398-5405
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Regions of High Antigenicity within the Hypothetical PPE Major Polymorphic Tandem Repeat Open- Reading Frame, Rv2608, Show a Differential Humoral Response and a Low T Cell Response in Various Categories of Patients with Tuberculosis.
P. Chakhaiyar, Y. Nagalakshmi, B. Aruna, K. J. R. Murthy, V. M. Katoch, and S. E. Hasnain (2004)
The Journal of Infectious Disease 190, 1237-1244
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