In vitro the mannose receptor (MR) mediates Ag internalization by dendritic cells (DC) and favors the presentation of mannosylated ligands to T cells. However, in vivo MR seems to play a role not in Ag presentation but in the homeostatic clearance of endogenous ligands, which could have the secondary benefit of reducing the levels of endogenous Ag available for presentation to the adaptive immune system. We have now observed that while MR+ cells are consistently absent from T cell areas of spleen and mesenteric lymph nodes (LN), peripheral LN of untreated adult mice contain a minor population of MR+ MHCII+ in the paracortex. This novel MR+ cell population can be readily identified by flow cytometry and express markers characteristic of DC. Furthermore, these MR+ DC-like cells located in T cell areas can be targeted with MR ligands (anti-MR mAb). Numbers of MR+ MHCII+ cells in the paracortex are increased upon stimulation of the innate immune system and, accordingly, the amount of anti-MR mAb reaching MR+ MHCII+ cells in T cell areas is dramatically enhanced under these conditions. Our results indicate that the MR can act as an Ag-acquisition system in a DC subpopulation restricted to lymphoid organs draining the periphery. Moreover, the effect of TLR agonists on the numbers of these MR+ DC suggests that the immunogenicity of MR ligands could be under the control of innate stimulation. In accordance with these observations, ligands highly specific for the MR elicit enhanced humoral responses in vivo only when administered in combination with endotoxin.