Mycobacteria target DC-SIGN to suppress dendritic cell function

Teunis B H Geijtenbeek, Sandra J Van Vliet, Estella A Koppel, Marta Sanchez-Hernandez, Christine M J E Vandenbroucke-Grauls, Ben Appelmelk, Yvette Van Kooyk

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Mycobacterium tuberculosis represents a world-wide health risk and immunosuppression is a particular problem in M. tuberculosis infections. Although macrophages are primarily infected, dendritic cells (DCs) are important in inducing cellular immune responses against M. tuberculosis. We hypothesized that DCs represent a target for M. tuberculosis and that the observed immuno-suppression results from modulation of DC functions. We demonstrate that the DC-specific C-type lectin DC-SIGN is an important receptor on DCs that captures and internalizes intact Mycobacterium bovis bacillus Calmette-Guérin (BCG) through the mycobacterial cell wall component ManLAM. Antibodies against DC-SIGN block M. bovis BCG infection of DCs. ManLAM is also secreted by M. tuberculosis-infected macrophages and has been implicated as a virulence factor. Strikingly, ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation. Both mycobacteria and LPS induce DC maturation through Toll-like receptor (TLR) signaling, suggesting that DC-SIGN, upon binding of ManLAM, interferes with TLR-mediated signals. Blocking antibodies against DC-SIGN reverse the ManLAM-mediated immunosuppressive effects. Our results suggest that M. tuberculosis targets DC-SIGN both to infect DCs and to down-regulate DC-mediated immune responses. Moreover, we demonstrate that DC-SIGN has a broader pathogen recognition profile than previously shown, suggesting that DC-SIGN may represent a molecular target for clinical intervention in infections other than HIV-1.

Original languageEnglish
Pages (from-to)7-17
Number of pages11
JournalJournal of Experimental Medicine
Volume197
Issue number1
Publication statusPublished - 6 Jan 2003

Cite this

Geijtenbeek, Teunis B H ; Van Vliet, Sandra J ; Koppel, Estella A ; Sanchez-Hernandez, Marta ; Vandenbroucke-Grauls, Christine M J E ; Appelmelk, Ben ; Van Kooyk, Yvette. / Mycobacteria target DC-SIGN to suppress dendritic cell function. In: Journal of Experimental Medicine. 2003 ; Vol. 197, No. 1. pp. 7-17.
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title = "Mycobacteria target DC-SIGN to suppress dendritic cell function",
abstract = "Mycobacterium tuberculosis represents a world-wide health risk and immunosuppression is a particular problem in M. tuberculosis infections. Although macrophages are primarily infected, dendritic cells (DCs) are important in inducing cellular immune responses against M. tuberculosis. We hypothesized that DCs represent a target for M. tuberculosis and that the observed immuno-suppression results from modulation of DC functions. We demonstrate that the DC-specific C-type lectin DC-SIGN is an important receptor on DCs that captures and internalizes intact Mycobacterium bovis bacillus Calmette-Gu{\'e}rin (BCG) through the mycobacterial cell wall component ManLAM. Antibodies against DC-SIGN block M. bovis BCG infection of DCs. ManLAM is also secreted by M. tuberculosis-infected macrophages and has been implicated as a virulence factor. Strikingly, ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation. Both mycobacteria and LPS induce DC maturation through Toll-like receptor (TLR) signaling, suggesting that DC-SIGN, upon binding of ManLAM, interferes with TLR-mediated signals. Blocking antibodies against DC-SIGN reverse the ManLAM-mediated immunosuppressive effects. Our results suggest that M. tuberculosis targets DC-SIGN both to infect DCs and to down-regulate DC-mediated immune responses. Moreover, we demonstrate that DC-SIGN has a broader pathogen recognition profile than previously shown, suggesting that DC-SIGN may represent a molecular target for clinical intervention in infections other than HIV-1.",
keywords = "Bacterial Adhesion, Binding Sites, Cell Adhesion Molecules/chemistry, Cell Division, Cells, Cultured, Dendritic Cells/immunology, Drosophila Proteins, Endocytosis, Glycolipids/metabolism, Humans, Immune Tolerance, Interleukin-10/metabolism, Lectins, C-Type/chemistry, Lipopolysaccharides/metabolism, Lysosomes/metabolism, Membrane Glycoproteins/metabolism, Mycobacterium tuberculosis/metabolism, Protein Binding, Receptors, Cell Surface/chemistry, Signal Transduction, Toll-Like Receptors",
author = "Geijtenbeek, {Teunis B H} and {Van Vliet}, {Sandra J} and Koppel, {Estella A} and Marta Sanchez-Hernandez and Vandenbroucke-Grauls, {Christine M J E} and Ben Appelmelk and {Van Kooyk}, Yvette",
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Mycobacteria target DC-SIGN to suppress dendritic cell function. / Geijtenbeek, Teunis B H; Van Vliet, Sandra J; Koppel, Estella A; Sanchez-Hernandez, Marta; Vandenbroucke-Grauls, Christine M J E; Appelmelk, Ben; Van Kooyk, Yvette.

In: Journal of Experimental Medicine, Vol. 197, No. 1, 06.01.2003, p. 7-17.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Mycobacteria target DC-SIGN to suppress dendritic cell function

AU - Geijtenbeek, Teunis B H

AU - Van Vliet, Sandra J

AU - Koppel, Estella A

AU - Sanchez-Hernandez, Marta

AU - Vandenbroucke-Grauls, Christine M J E

AU - Appelmelk, Ben

AU - Van Kooyk, Yvette

PY - 2003/1/6

Y1 - 2003/1/6

N2 - Mycobacterium tuberculosis represents a world-wide health risk and immunosuppression is a particular problem in M. tuberculosis infections. Although macrophages are primarily infected, dendritic cells (DCs) are important in inducing cellular immune responses against M. tuberculosis. We hypothesized that DCs represent a target for M. tuberculosis and that the observed immuno-suppression results from modulation of DC functions. We demonstrate that the DC-specific C-type lectin DC-SIGN is an important receptor on DCs that captures and internalizes intact Mycobacterium bovis bacillus Calmette-Guérin (BCG) through the mycobacterial cell wall component ManLAM. Antibodies against DC-SIGN block M. bovis BCG infection of DCs. ManLAM is also secreted by M. tuberculosis-infected macrophages and has been implicated as a virulence factor. Strikingly, ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation. Both mycobacteria and LPS induce DC maturation through Toll-like receptor (TLR) signaling, suggesting that DC-SIGN, upon binding of ManLAM, interferes with TLR-mediated signals. Blocking antibodies against DC-SIGN reverse the ManLAM-mediated immunosuppressive effects. Our results suggest that M. tuberculosis targets DC-SIGN both to infect DCs and to down-regulate DC-mediated immune responses. Moreover, we demonstrate that DC-SIGN has a broader pathogen recognition profile than previously shown, suggesting that DC-SIGN may represent a molecular target for clinical intervention in infections other than HIV-1.

AB - Mycobacterium tuberculosis represents a world-wide health risk and immunosuppression is a particular problem in M. tuberculosis infections. Although macrophages are primarily infected, dendritic cells (DCs) are important in inducing cellular immune responses against M. tuberculosis. We hypothesized that DCs represent a target for M. tuberculosis and that the observed immuno-suppression results from modulation of DC functions. We demonstrate that the DC-specific C-type lectin DC-SIGN is an important receptor on DCs that captures and internalizes intact Mycobacterium bovis bacillus Calmette-Guérin (BCG) through the mycobacterial cell wall component ManLAM. Antibodies against DC-SIGN block M. bovis BCG infection of DCs. ManLAM is also secreted by M. tuberculosis-infected macrophages and has been implicated as a virulence factor. Strikingly, ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation. Both mycobacteria and LPS induce DC maturation through Toll-like receptor (TLR) signaling, suggesting that DC-SIGN, upon binding of ManLAM, interferes with TLR-mediated signals. Blocking antibodies against DC-SIGN reverse the ManLAM-mediated immunosuppressive effects. Our results suggest that M. tuberculosis targets DC-SIGN both to infect DCs and to down-regulate DC-mediated immune responses. Moreover, we demonstrate that DC-SIGN has a broader pathogen recognition profile than previously shown, suggesting that DC-SIGN may represent a molecular target for clinical intervention in infections other than HIV-1.

KW - Bacterial Adhesion

KW - Binding Sites

KW - Cell Adhesion Molecules/chemistry

KW - Cell Division

KW - Cells, Cultured

KW - Dendritic Cells/immunology

KW - Drosophila Proteins

KW - Endocytosis

KW - Glycolipids/metabolism

KW - Humans

KW - Immune Tolerance

KW - Interleukin-10/metabolism

KW - Lectins, C-Type/chemistry

KW - Lipopolysaccharides/metabolism

KW - Lysosomes/metabolism

KW - Membrane Glycoproteins/metabolism

KW - Mycobacterium tuberculosis/metabolism

KW - Protein Binding

KW - Receptors, Cell Surface/chemistry

KW - Signal Transduction

KW - Toll-Like Receptors

M3 - Article

VL - 197

SP - 7

EP - 17

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 1

ER -

Geijtenbeek TBH, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M, Vandenbroucke-Grauls CMJE, Appelmelk B et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. Journal of Experimental Medicine. 2003 Jan 6;197(1):7-17.