A novel role of complement factor C1q in augmenting the presentation of antigen captured in immune complexes to CD8+ T lymphocytes.

Ag-IgG immune complexes (IC) are efficiently taken up, and Ag-derived peptides are subsequently processed and presented by APC. In vitro experiments indicate that IgG Fc Receptors (FcgammaR) facilitate the efficient uptake of IC by dendritic cells. Previous experiments showed that the cross-presentation of Ag-derived peptides after s.c. administration of IC is FcgammaR-dependent. To study the role of different FcgammaR and complement in MHC class I Ag presentation after i.v. administration, we used mice deficient for FcgammaRs and complement components. These mice were injected with CFSE-labeled OVA-specific CD8+ T cells followed by administration of IC composed of OVA and rabbit anti-OVA IgG i.v. to measure MHC class I presentation of OVA-derived peptides. The Ag presentation was partly reduced in FcRgamma-chain-deficient mice, but not affected in FcgammaRI/II/III-deficient mice, complement factor C3-deficient mice, or FcgammaRI/II/III x C3-deficient mice. Importantly, CD8+ T cell proliferation was significantly reduced in mice deficient for C1q. This proliferation could be restored when IC were incubated with purified human C1q before injection. Likewise, purified C1q could strongly enhance the uptake and presentation of IC by dendritic cells in vitro. Heat inactivation abrogated the C1q-mediated uptake of IC. In addition, in vivo uptake of OVA-IC in the spleen was significantly reduced in C1q-deficient mice compared with wild-type mice. Together, these results indicate a novel function of C1q, which is present in high levels in the bloodstream, by directly enhancing the uptake and MHC class I presentation of Ag captured in IC by APC to CD8+ T cells.

Dendritic cells, but not macrophages or B cells, activate major histocompatibility complex class II-restricted CD4+ T cells upon immune-complex uptake in vivo.

Professional antigen-presenting cells (APC) are able to process and present exogenous antigen leading to the activation of T cells. Antigen-immunoglobulin (Ig)G complexes (IC) are much more efficiently processed and presented than soluble antigen. Dendritic cells (DC) are known for their ability to take up and process immune complex (IC) via FcgammaR, and they have been shown to play a crucial role in IC-processing onto major histocompatibility complex (MHC) class I as they contain a specialized cross-presenting transport system required for MHC class I antigen-processing. However, the MHC class II-antigen-processing pathway is distinct. Therefore various other professional APC, like macrophages and B cells, all displaying FcgammaR, are thought to present IC-delivered antigen in MHC class II. Nonetheless, the relative contribution of these APC in IC-facilitated antigen-presentation for MHC class II in vivo is not known. Here we show that, in mice, both macrophages and DC, but not B cells, efficiently capture IC. However, only DC, but not macrophages, efficiently activate antigen-specific MHC class II restricted CD4(+) T cells. These results indicate that mainly DC and not other professional APC, despite expressing FcgammaR and MHC class II, contribute significantly to IC-facilitated T cell activation in vivo under steady-state conditions.

Murine Fc receptors for IgG are redundant in facilitating presentation of immune complex derived antigen to CD8+ T cells in vivo.

Antigen(Ag)-immunoglobulin (Ig)G complexes (IC) are more efficiently processed and presented than soluble Ag. IC can bind to various cell types via different types of Fc-Receptors or, upon binding to complement factors, by complement receptors. Murine professional antigen-presenting cells (APC) express four types of FcgammaReceptors (FcgammaR) via which they are able to capture IC; three activating receptors (FcgammaRI, III and IV) and one inhibitory receptor (FcgammaRII). It has been demonstrated that FcgammaR play a pivotal role in facilitating the presentation of Ag derived from IC. Nonetheless, relative little information is available on the relative contribution of the activating or inhibitory FcgammaR or complement to the presentation of immune-complexed Ag to CD8+ T cells. To study the contribution of the different FcgammaR and complement receptors in IC-facilitated Ag-presentation, we analyzed the ovalbumin(OVA)-specific CD8+ T cell proliferation in FcgammaR- and complement component 3 (C3)-deficient mice after subcutaneous injection of OVA-IC. Here we show that the efficient Ag-presentation was FcgammaR-, but not C3-mediated, as it was inhibited in FcgammaRI/II/III-deficient mice but unaffected in the C3-depleted mice. Moreover, FcgammaRIV does not play a role under these conditions. However, no difference was found between wild-type and FcgammaRI/III-deficient or wild-type and FcgammaRII-deficient mice. These results indicate that Ag-presentation via the activating FcgammaR is not enhanced in the absence of FcgammaRII, and point to redundancy of the FcgammaR, including FcgammaRII, in the uptake and presentation of s.c. injected soluble IC to CD8+ T cells.