Immunology of cutaneous leishmaniasis: the role of mast cells, phagocytes and dendritic cells for protective immunity.

Millions of Leishmania major infections in humans are reported worldwide. In experimental infections, various phagocytes predominant in skin--neutrophils, macrophages (MPhi) and dendritic cells (DC)--play very distinct roles for the hosts' immune response against L. major infection and they are sequentially engaged via different pathogen recognition receptors as cutaneous leishmaniasis evolves. In the initial "silent" phase without clinically apparent inflammation, L. major promastigotes are primarily phagocytosed by resident MPhi via CR3. Upon activation of cutaneous mast cells, inflammatory neutrophils and monocytes are recruited to the skin coincident with the development of a nodular plaque. Later on, in established infections, DC-, B cell- and T cell-dependent immunity becomes critically important for lesion resolution. Antibody-mediated uptake of L. major by DC leads to IL-12 production and priming of Th1/Tc1 cells, both of which are required for efficient parasite killing by lesional MPhi. Finally, Fc receptor-mediated uptake of L. major by MPhi induces counter-regulatory IL-10 production leading to parasite persistence. Thus, the balance between CR3- and FcgammaR-triggered anti- and proinflammatory mechanisms involving MPhi and DC is critical for disease outcome. This review highlights the importance of the various phagocytes for the development of anti-Leishmania immunity.