The study investigates the interaction between *Mycobacterium tuberculosis* and dendritic cells (DCs), focusing on the role of DC-SIGN, a C-type lectin expressed on DCs. The authors demonstrate that DC-SIGN captures and internalizes intact *Mycobacterium bovis* bacillus Calmette-Guérin (BCG) through the mycobacterial cell wall component ManLAM. Antibodies against DC-SIGN block BCG infection of DCs. ManLAM is also secreted by *M. tuberculosis*-infected macrophages and has been implicated as a virulence factor. Notably, ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation, suggesting that DC-SIGN interferes with TLR-mediated signals. Blocking antibodies against DC-SIGN reverse the immunosuppressive effects mediated by ManLAM. The findings indicate that *M. tuberculosis* targets DC-SIGN to infect DCs and to down-regulate DC-mediated immune responses, providing a potential molecular target for clinical intervention in infections other than HIV-1.The study investigates the interaction between *Mycobacterium tuberculosis* and dendritic cells (DCs), focusing on the role of DC-SIGN, a C-type lectin expressed on DCs. The authors demonstrate that DC-SIGN captures and internalizes intact *Mycobacterium bovis* bacillus Calmette-Guérin (BCG) through the mycobacterial cell wall component ManLAM. Antibodies against DC-SIGN block BCG infection of DCs. ManLAM is also secreted by *M. tuberculosis*-infected macrophages and has been implicated as a virulence factor. Notably, ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation, suggesting that DC-SIGN interferes with TLR-mediated signals. Blocking antibodies against DC-SIGN reverse the immunosuppressive effects mediated by ManLAM. The findings indicate that *M. tuberculosis* targets DC-SIGN to infect DCs and to down-regulate DC-mediated immune responses, providing a potential molecular target for clinical intervention in infections other than HIV-1.