Plasmacytoid dendritic cells of melanoma patients present exogenous proteins to CD4+ T cells after FcγRII-mediated uptake

Abstract

Plasmacytoid dendritic cells (pDCs) contribute to innate antiviral immune responses by producing type I interferons. Although human pDCs can induce T cell responses upon viral infection, it remains unclear if pDCs can present exogenous antigens. Here, we show that human pDCs exploit FcγRII (CD32) to internalize antigen–antibody complexes, resulting in the presentation of exogenous antigen to T cells. pDCs isolated from melanoma patients vaccinated with autologous monocyte-derived peptide- and keyhold limpet hemocyanin (KLH)–loaded dendritic cells, but not from nonvaccinated patients or patients that lack a humoral response against KLH, were able to stimulate KLH-specific T cell proliferation. Interestingly, we observed that internalization of KLH by pDCs depended on the presence of serum from vaccinated patients that developed an anti-KLH antibody response. Anti-CD32 antibodies inhibited antigen uptake and presentation, demonstrating that circulating anti-KLH antibodies binding to CD32 mediate KLH internalization. We conclude that CD32 is an antigen uptake receptor on pDCs and that antigen presentation by pDCs is of particular relevance when circulating antibodies are present. Antigen presentation by pDCs may thus modulate the strength and quality of the secondary phase of an immune response.

Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE

“…We could not find any signs of altered ICOS signaling in the T cells after pDC depletion and we conclude that ICOS ligand-ICOS interactions between pDC and Th cells are unlikely to cause the observed phenotype. (iv) It is believed that pDC has limited capacity to present exogenous Ag via MHC class II [11], although pDC can internalize exogenous Ag-Ab complexes via CD32 and subsequently present Ag on MHC class II [33]. However, at this stage we can neither confirm nor exclude a role for pDC in Ag-presentation in EAE.…”

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

“…Previously we have demonstrated that DCIR and FcgRII-mediated uptake of KLH protein induces efficient Ag presentation by human pDCs (15,30). In this study, we showed that human pDCs are capable of processing phagocytosed particulate Ag, and in addition can be activated by particulate TLR-Ls.…”

“…Activated pDCs have been demonstrated to promote Th1 (31,47) as well as Th2 responses (32,33), underlining their remarkable functional plasticity. The pDCs were shown to prime specific CD4 + and CD8 + lymphocytes against endogenous and exogenous Ags (15,48), viruses (49) and tumor Ags (45). By contrast, when activated by CpG-B pDCs demonstrate a strong immune suppression and induce the differentiation of allogeneic CD4 + CD25 2 T cells into CD4 + CD25 + regulatory T cells (32).…”

“…pDCs can take up and present soluble Ags from their environment, but this seems to require specific receptor-mediated endocytosis, as their macropinocytic capacity is poor (13,14). We recently reported that pDCs are able to internalize soluble exogenous Ag bound to Agspecific Abs via the FcgRIIa receptor, resulting in CD4 + T cell activation (15).…”

Antigen Delivery to Plasmacytoid Dendritic Cells via BST2 Induces Protective T Cell-Mediated Immunity

“…They may therefore be specialized to present Ags, which are available for MHC II loading for longer time periods (such as in viral infection), whereas they are rather poor at presenting soluble Ags (20,21). However, presentation of exogenous Ags to CD4 + T cells in vitro can be achieved by Ag delivery to human PDCs via FcgRIIA (22) or DCIR, for example (23). PDCs have also been demonstrated to cross-present viral Ags derived from infected cells or directly from viral particles to CD8 + T cells in vitro (24)(25)(26), although it is still controversial if this also occurs in vivo (20).…”