Leishmania amazonensis - Dendritic cell interactions in vitro and the priming of parasite-specific CD4(+) T cells in vivo

The progressive disease following Leishmania amazonensis infection in mice requires functional CD4+ T cells, which are primed to a disease-promoting p henotype during the infection. To understand how these pathogenic T cells a re generated and the role of dendritic cells (DCs) in this process, we use DCs of susceptible BALB/c and resistant C3H/HeJ mice to examine parasite-DC interactions in vitro as well as the effector phenotype of T cells primed by parasite-exposed DCs in vivo. Our results demonstrate that amastigotes a nd metacyclics efficiently enter and activate DCs of both genetic backgroun ds. Infection with amastigotes fails to induce CD40-depedent IL-12 producti on, but rather potentiates IL-4 production in BALB/c DCs. Upon transfer int o syngeneic recipients, amastigote-exposed BALB/c DCs prime parasite-specif ic Th cells to produce significantly higher levels of IL-4 and IL-10 than t heir C3H/HeJ counterparts. Transfer studies with IL-4(-/-) DCs indicate tha t this enhanced Th2 priming seen in BALB/c mice is partially due to the IL- 4 production by amastigote-carrying DCs. These results suggest that L amazo nensis amastigotes may condition DCs of a susceptible host to a state that favors activation of pathogenic CD4(+) T cells, and thereby provide a new p erspective on the pathogenesis of cutaneous leishmaniasis and protozoan par asite-host interactions in general.