UPTAKE OF LEISHMANIA-MAJOR AMASTIGOTES RESULTS IN ACTIVATION AND INTERLEUKIN-12 RELEASE FROM MURINE SKIN-DERIVED DENDRITIC CELLS - IMPLICATIONS FOR THE INITIATION OF ANTI-LEISHMANIA IMMUNITY

Epidermal Langerhans cells (LC) are immature dendritic cells (DC) loca ted in close proximity to the site of inoculation of infectious Leishm ania major metacyclic promastigotes by sand flies. Using LC-like DC ex panded from C57BL/6 fetal skin, we characterized interactions involvin g several developmental stages of Leishmania and DC. We confirmed that L. major amastigotes, but not promastigotes, efficiently entered LC-l ike DC. Parasite internalization was associated with activation manife sted by upregulation of major histocompatibility complex (MHC) class I and II surface antigens, increased expression of costimulatory molecu les (CD40, CD54, CD80, and CD86), and interleukin (IL)-12 p40 release within 18 h. L. major-induced IL-12 p70 release by DC required interfe ron gamma and prolonged (72 h) incubation. In contrast, infection of i nflammatory macrophages (M phi) with amastigotes or promastigotes did not lead to significant changes in surface antigen expression or cytok ine production. These results suggest that skin M phi and DC are infec ted sequentially in cutaneous leishmaniasis and that they play distinc t roles in the inflammatory and immune response initiated by L. major M phi capture organisms near the site of inoculation early in the cour se of infection after establishment of cellular immunity, and kill ama stigotes but probably do not actively participate in T cell priming. I n contrast, skin DC are induced to express increased amounts of MHC an tigens and costimulatory molecules and to release cytokines (including IL-12 p70) by exposure to L. major amastigotes that ultimately accumu late in lesional tissue, and thus very likely initiate protective T he lper cell type 1 immunity.