Skin mast cells control T cell-dependent host defense in Leishmania major infections.

Mast cells (MCs) initiate protective immunity against bacteria. Here we demonstrate that MCs also contribute to the control of parasitic skin infections by Leishmania major. L. major-infected MC-deficient Kit(W)/Kit(W-v) mice developed markedly larger skin lesions than did normal Kit+/+ mice (>2-fold), and cutaneous reconstitution with MCs resulted in normalization of lesion development. Kit(W)/Kit(W-v) lesions contained significantly more parasites, and infections resulted in enhanced spreading of parasites to the spleens as compared to controls. In addition, recruitment of proinflammatory neutrophils, macrophages, and dendritic cells (DCs) in infected mice was MC dependent. In the absence of MCs, reduced numbers of lesional DCs were associated with decreased production of Th1-promoting interleukin (IL)-12. Antigen-specific T cell priming was delayed in Kit(W)/Kit(W-v) mice and cytokine responses were skewed towards Th2. Notably, local skin MC reconstitution at sites of infection was sufficient for the induction of systemic protection. Thus, MC-mediated control of L. major infections is not limited to the induction of local inflammation. Instead, MCs contribute significantly to local DC recruitment, which mediates protective immunity. These findings extend the view of MCs as salient sentinels of innate immunity to complex host defense reactions against intracellular pathogens.

Uptake of Leishmania major by dendritic cells is mediated by Fcgamma receptors and facilitates acquisition of protective immunity.

Uptake of Leishmania major by dendritic cells (DCs) results in activation and interleukin (IL)-12 release. Infected DCs efficiently stimulate CD4- and CD8- T cells and vaccinate against leishmaniasis. In contrast, complement receptor 3-dependent phagocytosis of L. major by macrophages (MPhi) leads exclusively to MHC class II-restricted antigen presentation to primed, but not naive, T cells, and no IL-12 production. Herein, we demonstrate that uptake of L. major by DCs required parasite-reactive immunoglobulin (Ig)G and involved FcgammaRI and FcgammaRIII. In vivo, DC infiltration of L. major-infected skin lesions coincided with the appearance of antibodies in sera. Skin of infected B cell-deficient mice and Fcgamma-/- mice contained fewer parasite-infected DCs in vivo. Infected B cell-deficient mice as well as Fcgamma-/- mice (all on the C57BL/6 background) showed similarly increased disease susceptibility as assessed by lesion volumes and parasite burdens. The B cell-deficient mice displayed impaired T cell priming and dramatically reduced IFN-gamma production, and these deficits were normalized by infection with IgG-opsonized parasites. These data demonstrate that DC and MPhi use different receptors to recognize and ingest L. major with different outcomes, and indicate that B cell-derived, parasite-reactive IgG and DC FcgammaRI and FcgammaRIII are essential for optimal development of protective immunity.