Mycobacteria target DC-SIGN to suppress dendritic cell function. Mycobacterium tuberculosis is a global health threat, and immune suppression is a major issue in infections. Although macrophages are primarily infected, dendritic cells (DCs) are crucial for inducing immune responses against M. tuberculosis. The study shows that DCs are a target for M. tuberculosis, and immune suppression results from modulation of DC functions. DC-SIGN, a C-type lectin specific to DCs, is an important receptor 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 is a virulence factor. 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. The results suggest that M. tuberculosis targets DC-SIGN both to infect DCs and to down-regulate DC-mediated immune responses. Additionally, DC-SIGN has a broader pathogen recognition profile than previously shown, suggesting it may be a molecular target for clinical intervention in infections other than HIV-1. The study demonstrates that DC-SIGN is an important receptor for mycobacteria on DCs, and that ManLAM is internalized by DC-SIGN and targeted to lysosomes. ManLAM binding to DC-SIGN also inhibits DC activation and induces the immunosuppressive cytokine IL-10, promoting immunosuppression and aiding mycobacterial survival. These findings highlight the role of DC-SIGN in modulating immune responses and suggest that targeting DC-SIGN could be a strategy to combat M. tuberculosis infections.Mycobacteria target DC-SIGN to suppress dendritic cell function. Mycobacterium tuberculosis is a global health threat, and immune suppression is a major issue in infections. Although macrophages are primarily infected, dendritic cells (DCs) are crucial for inducing immune responses against M. tuberculosis. The study shows that DCs are a target for M. tuberculosis, and immune suppression results from modulation of DC functions. DC-SIGN, a C-type lectin specific to DCs, is an important receptor 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 is a virulence factor. 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. The results suggest that M. tuberculosis targets DC-SIGN both to infect DCs and to down-regulate DC-mediated immune responses. Additionally, DC-SIGN has a broader pathogen recognition profile than previously shown, suggesting it may be a molecular target for clinical intervention in infections other than HIV-1. The study demonstrates that DC-SIGN is an important receptor for mycobacteria on DCs, and that ManLAM is internalized by DC-SIGN and targeted to lysosomes. ManLAM binding to DC-SIGN also inhibits DC activation and induces the immunosuppressive cytokine IL-10, promoting immunosuppression and aiding mycobacterial survival. These findings highlight the role of DC-SIGN in modulating immune responses and suggest that targeting DC-SIGN could be a strategy to combat M. tuberculosis infections.