Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: Evidence for a negative signal delivered through the mannose receptor

IL-12 is a key cytokine in directing the development of type I Th cells, wh ich are critical to eradicate intracellular pathogens such as Mycobacterium tuberculosis. Here, we report that mannose-capped lipoarabinomarmans (ManL AMs) from Mycobacterium bovis bacillus Calmette-Guerin and Mycobacterium tu berculosis inhibited, in a dose-dependant manner, the LPS-induced IL-12 pro duction by human dendritic cells. The inhibitory activity was abolished by the loss of the mannose caps or the GPI acyl residues. Mannan, which is a l igand for the mannose receptor (MR) as well as an mAb specific for the MR, also inhibited the LPS-Induced IL-12 production by dendritic cells. Our res ults indicate that ManLAMs may act as virulence factors that contribute to the persistence of M. bovis bacillus Calmette-Guerin and M. tuberculosis wi thin phagocytic cells by suppressing IL-12 responses. Our data also suggest that engagement of the MR by ManLAMs delivers a negative signal that inter feres with the LPS-induced positive signals delivered by the Toll-like rece ptors.