ABSTRACTThe usual agent of visceral leishmaniasis in the Old World isLeishmania donovani, which typically produces systemic diseases in humans and mice.L. donovanihas developed efficient strategies to infect and persist in macrophages from spleen and liver. Dendritic cells (DC) are sentinels of the immune system. Following recognition of evolutionary conserved microbial products, DC undergo a maturation process and activate antigen-specific naïve T cells. In the present report we provide new insights into how DC detectLeishmaniain vivo. We demonstrate that in both C57BL/6 and BALB/c mice, systemic injection ofL. donovaniinduced the migration of splenic DC from marginal zones to T-cell areas. During migration, DC upregulated the expression of major histocompatibility complex II and costimulatory receptors (such as CD40, CD80, and CD86).Leishmania-induced maturation requires live parasites and is not restricted toL. donovani, asL. braziliensis,L. major, andL. mexicanainduced a similar process. Using a green fluorescent protein-expressing parasite, we demonstrate that DC undergoing maturation in vivo display no parasite internalization. We also show thatL. donovani-induced DC maturation was partially abolished in MyD88-deficient mice. Taken together, our data suggest thatLeishmania-induced DC maturation results from direct recognition ofLeishmaniaby DC, and not from DC infection, and that MyD88-dependent receptors are implicated in this process.