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Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Immunex Corporation, Seattle, WA 98101
Leishmaniasis, a vector-borne parasitic disease, is transmitted
during a sandfly blood meal as the parasite is delivered into the
dermis. The parasite displays a unique immune evasion mechanism:
prevention of IL-12 production within its host cell, the macrophage
(i.e., where it differentiates and multiplies). Given the close
proximity of skin dendritic cells (DC) to the site of parasite
delivery, their critical role in initiating immune responses and the
self-healing nature of Leishmania major (Lm) infection,
we examined the interaction between myeloid-derived human DC and Lm
metacyclic promastigotes (infectious-stage parasites) to model the
early "natural" events of infection. We found that DC can take up
Lm and, after this internalization, undergo changes in surface
phenotype suggesting "maturation". Despite the intracellular
location of the parasite and resultant up-regulation of costimulatory
and class II molecules, there was no detectable cytokine release by
these Lm-harboring DC. However, using intracellular staining and flow
cytometry to analyze cytokine production at the single-cell level, we
found that Lm-harboring DC, but not monocytes, produce large amounts of
IL-12p70 in a CD40 ligand (CD40L)-dependent manner. Finally, DC
generated from mononuclear cells from patients with cutaneous
leishmaniasis (Lm), once loaded with live metacyclic promastigotes,
were found to reactivate autologous primed T lymphocytes and induce a
CD40L-dependent IFN-
response. Our results link the required
CD40/CD40L interactions for healing with DC-derived IL-12p70 production
and provide a mechanism to explain the genesis of a protective T
cell-mediated response in the face of local immune evasion within the
macrophage at the site of Leishmania
delivery.
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