Processing of Leishmania dononvani by human dendritic cells

Abstract

Leishmania parasites are intracellular protiststhat cause various human diseases ranging from self-healing cutaneous to fatal visceral leishmaniasis. The host cells are phagocytes, primarily neutrophils and macrophages, where the parasites neutralize innate immune defenses, proliferate and finally infect other cells. Despite that Leishmania induce vigorous T cell responses, which require antigen presentation and stimulation by phagocytes, importantly dendritic cells. So far it is not clear how to align the blockade of phagocyte functions with the efficient immune stimulation. We found that, in contrast to other phagocytes, human dendritic cells digest the parasites through an apoptotic process, granzyme B and maybe granulysin manage this killing, and digestion of parasites is delayed in granzyme B inhibited cells. The digested parasites co-localise with components of the MHC class I and II antigen processing pathways. Furthermore, the infection leads to enhanced activation of dendritic cells triggered by inflammatory cytokines. The data presented herein emphasize the need to address the DCs when developing anti-Leishmania vaccines or immunotherapies in order to induce efficient CD4+ helper and CD8 effector T cell responses. They may explain why leishmanization, i.e. immunization with life parasites, is efficient whereas subunit vaccines are not. However, leishmanization induces immunity through deliberate infection with subsequent disease, which may come with severe adverse effects. Alternative strategies may consider TLR agonists or inflammatory cytokines for in situ vaccination and immunotherapy to activate parasite-bearing DCs and thereby induce parasitocidal CD8 effector T cell and innate immune reaction.