AbstractDendritic cells have an important role in immune surveillance. After being exposed to microbial components, they migrate to secondary lymphoid organs and activate T lymphocytes. Here we show that during mouse malaria, splenic inflammatory monocytes differentiate into monocyte-derived dendritic cells (MO-DCs), which are CD11b⁺F4/80⁺CD11c⁺MHCII^highDC-SIGN^highLy6c⁺ and express high levels of CCR5, CXCL9 and CXCL10 (CCR5⁺CXCL9/10⁺ MO-DCs). We propose that malaria-induced splenic MO-DCs take a reverse migratory route. After differentiation in the spleen, CCR5⁺CXCL9/10⁺ MO-DCs traffic to the brain in a CCR2-independent, CCR5-dependent manner, where they amplify the influx of CD8⁺ T lymphocytes, leading to a lethal neuropathological syndrome.