Mycobacteria Target DC-SIGN to Suppress Dendritic Cell Function

By Teunis B. Geijtenbeek, S. V. van Vliet, E. Koppel, M. Sánchez-Hernández, C. Vandenbroucke-Grauls, B. Appelmelk, Y. van Kooyk. Journal of Experimental Medicine, 2003

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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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/0d403d046c5896c644795816de58ab47821534ed

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Citations in the corpus

The Continuing Challenges of Leprosy (2006, background): “In contrast, increases in the expression of IL-6, IL-8, and IL-10 mRNAs and sustained expression of IL-4 and IL-5 mRNAs, all cytokines associated with neutrophil chemotaxis, antibody production, and reduced cell-mediated immunity, were observed in ENL lesions.”
Signalling through C-type lectin receptors: shaping immune responses (2009, background): “The interaction of DC-sIGN with mannose-containing pathogens, such as Mycobacterium tuberculosis, Mycobacterium leprae, HIv-1, measles virus and Candida albicans, affects TLR4-mediated immune responses by DCs 3, 20 .”
Dectin-1: a signalling non-TLR pattern-recognition receptor (2006, background): “, might induce IL-10 production in LPS-activated DCs in a SYK-dependent manner, in response to mycobacterial lipoarabinomannan”
Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle (2009, background): “, 2003), but its binding results in the down-regulation of dendritic cell–mediated immune responses (Geijtenbeek et al., 2003).”
An integrated model of the recognition of Candida albicans by the innate immune system (2008, background): “Modulation of DC function can also be a target for escape mechanisms, with the MR and DC-SIGN possibly inducing anti-inflammatory cytokine production and immunosuppressio”
Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209+ dendritic cells for immune T cell areas (2010, background): “, 2002) or in transducing inhibitory signals as seen when human DC-SIGN/CD209 interacts with mycobacteria (Geijtenbeek et al., 2003; Tailleux et al., 2003).”
Candida albicans morphogenesis and host defence: discriminating invasion from colonization (2011, positive): “Although DC-SIGN can induce immunosuppression by stimulating IL-10 productio”