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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}mail.ncifcrf.gov

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

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Pulmonary Dendritic Cells.
K. Vermaelen and R. Pauwels (2005)
172, 530-551
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
BACTERIAL INTERACTIONS WITH CELLS OF THE INTESTINAL MUCOSA: TOLL-LIKE RECEPTORS AND NOD2.
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Antimicrobial proteins and peptides: anti-infective molecules of mammalian leukocytes.
O. Levy (2004)
J. Leukoc. Biol. 76, 909-925
   Abstract »    Full Text »    PDF »
{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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
{beta}-Defensin Expression in Immunocompetent and Immunodeficient Germ-Free and Candida albicans-Monoassociated Mice.
D. A. Schofield, C. Westwater, and E. Balish (2004)
The Journal of Infectious Disease 190, 1327-1334
   Abstract »    Full Text »    PDF »
Endogenous ligands of Toll-like receptors.
M.-F. Tsan and B. Gao (2004)
J. Leukoc. Biol. 76, 514-519
   Abstract »    Full Text »    PDF »
Temporin A and Related Frog Antimicrobial Peptides Use Formyl Peptide Receptor-Like 1 as a Receptor to Chemoattract Phagocytes.
Q. Chen, D. Wade, K. Kurosaka, Z. Y. Wang, J. J. Oppenheim, and D. Yang (2004)
J. Immunol. 173, 2652-2659
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Enhanced Surfactant Protein and Defensin mRNA Levels and Reduced Viral Replication during Parainfluenza Virus Type 3 Pneumonia in Neonatal Lambs.
B. Grubor, J. M. Gallup, D. K. Meyerholz, E. C. Crouch, R. B. Evans, K. A. Brogden, H. D. Lehmkuhl, and M. R. Ackermann (2004)
Clin. Vaccine Immunol. 11, 599-607
   Abstract »    Full Text »    PDF »
Toll-like receptors: function and roles in lung disease.
S. Basu and M. J. Fenton (2004)
Am J Physiol Lung Cell Mol Physiol 286, L887-L892
   Abstract »    Full Text »    PDF »

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