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J. Biol. Chem., Vol. 283, Issue 29, 20590-20599, July 18, 2008

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Dendritic Cell Interaction with Candida albicans Critically Depends on N-Linked Mannan^*

Alessandra Cambi¹, Mihai G. Netea², Hector M. Mora-Montes^¶, Neil A. R. Gow^¶3, Stanleyson V. Hato⁴, Douglas W. Lowman^||**, Bart-Jan Kullberg, Ruurd Torensma, David L. Williams^**, and Carl G. Figdor⁵

From the Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences and the Department of Medicine and Nijmegen University Centre for Infectious Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, the ^¶School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom, the ^||Corporate Analytical Services, Eastman Chemical Company, Kingsport, Tennessee 37662-5150, and the ^**Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614

The fungus Candida albicans is the most common cause of mycotic infections in immunocompromised hosts. Little is known about the initial interactions between Candida and immune cell receptors, because a detailed characterization at the structural level is lacking. Antigen-presenting dendritic cells (DCs), strategically located at mucosal surfaces and in the skin, may play an important role in anti-Candida protective immunity. However, the contribution of the various Candida-associated molecular patterns and their counter-receptors to DC function remains unknown. Here, we demonstrate that two C-type lectins, DC-SIGN and the macrophage mannose receptor, specifically mediate C. albicans binding and internalization by human DCs. Moreover, by combining a range of C. albicans glycosylation mutants with receptor-specific blocking and cytokine production assays, we determined that N-linked mannan but not O-linked or phosphomannan is the fungal carbohydrate structure specifically recognized by both C-type lectins on human DCs and directly influences the production of the proinflammatory cytokine IL-6. Better insight in the carbohydrate recognition profile of C-type lectins will ultimately provide relevant information for the development of new drugs targeting specific fungal cell wall antigens.

Received for publication, November 14, 2007 , and in revised form, March 13, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Public Health Service Grants GM53522 from NIGMS and AI45829 from NIAID (to D. L. W.). This work was also supported by NWO-TOP Grant 9120.6030 (to C. G. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S6 and Table S1.

¹ Recipient of a NWO VENI Grant 916.66.028 from the Netherlands Organization of Scientific Research.

² Supported by a VIDI grant of the Netherlands Organization of Scientific Research.

³ Supported by the Wellcome Trust (080088).

⁴ Present address: Dept. of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

⁵ To whom correspondence should be addressed: Dept. of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Postbox 9101, 6500 HB Nijmegen, The Netherlands. Tel.: 31-24-3617600; Fax: 31-24-3540339; E-mail: c.figdor{at}ncmls.ru.nl.

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