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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.

Mucosal tolerance prevents the body from eliciting productive immune responses against harmless Ags that enter the body via the mucosae, and is mediated by the induction of regulatory T cells that differentiate in the mucosa-draining lymph nodes (LN) under defined conditions of Ag presentation. In this study, we show that mice deficient in FcgammaRIIB failed to develop mucosal tolerance to OVA, and demonstrate in vitro and in vivo a critical role for this receptor in modulating the Ag-presenting capacity of dendritic cells (DC). In vitro it was shown that absence of FcgammaRIIB under tolerogenic conditions led to increased IgG-induced release of inflammatory cytokines such as MCP-1, TNF-alpha, and IL-6 by bone marrow-derived DC, and increased their expression of costimulatory molecules, resulting in an altered immunogenic T cell response associated with increased IL-2 and IFN-gamma secretion. In vivo we could show enhanced LN-DC activation and increased numbers of Ag-specific IFN-gamma-producing T cells when FcgammaRIIB(-/-) mice were treated with OVA via the nasal mucosa, inferring that DC modulation by FcgammaRIIB directed the phenotype of the T cell response. Adoptive transfer of CD4(+) T cells from the spleen of FcgammaRIIB(-/-) mice to naive acceptor mice demonstrated that OVA-responding T cells failed to differentiate into regulatory T cells, explaining the lack of tolerance in these mice. Our findings demonstrate that signaling via FcgammaRIIB on DC, initiated by local IgG in the mucosa-draining LN, down-regulates DC activation induced by nasally applied Ag, resulting in those defined conditions of Ag presentation that lead to Tr induction and tolerance.

Dendritic cells (DC) sense saprophytic yeast and pathogenic, filamentous forms of Candida albicans in a specific way, resulting in disparate patterns of DC and T(h) cell activation. Using human and murine DC, such disparate patterns could be traced to the exploitation of distinct recognition receptors. Although usage of mannose receptors led to protective type 1 responses in mice, entry through Fcgamma receptors was responsible for suppression of mannose receptor-dependent reactivity, onset of type 2 responses and associated pathology. As the usage of distinct receptors selectively occurred with yeast or hyphal forms of the fungus, these findings suggest that the responsibility for pathogenicity of C. albicans is shared by the organism and DC, with implications for fungal virulence, immunity and vaccine development.

Dendritic cells (DCs) are the only APCs capable of initiating adaptive immune responses. The initiation of immune responses requires that DCs 1) internalize and present Ags; and 2) undergo a differentiation process, called "maturation", which transforms DCs into efficient APCs. DC maturation may be initiated by the engagement of different surface receptors, including certain cytokine receptors (such as TNFR), Toll-like receptors, CD40, and FcRs. The early activation events that link receptor engagement and DC maturation are not well characterized. We found that FcR engagement by immune complexes induced the phosphorylation of Syk, a protein tyrosine kinase acting immediately downstream of FcRs. Syk was dispensable for DC differentiation in vitro and in vivo, but was strictly required for immune complexes internalization and subsequent Ag presentation to T lymphocytes. Importantly, Syk was also required for the induction of DC maturation and IL-12 production after FcR engagement, but not after engagement of other surface receptors, such as TNFR or Toll-like receptors. Therefore, protein tyrosine phosphorylation by Syk represents a novel pathway for the induction of DC maturation.