Rheumatoid arthritis is characterized by the presence of autoantibodies. Various animal models for arthritis have shown a critical role for antibodies in the induction and progression of the disease, with complement and Fc receptors as the key effector mechanisms activated by antigen–antibody immune complexes (IC) in the effector phase of the disease. Although they are required for the perpetuation of the disease, the possible mechanisms by which Fc receptors could contribute to the chronic inflammation in arthritis are still unclear. It is known, however, that crosslinking FcγR on effector cells induces a variety of cellular responses, ranging from phagocytosis to secretion of inflammatory mediators and antibody-dependent cell cytotoxicity. Furthermore, FcγRs on dendritic cells (DC) are involved in the enhanced MHC class II-restricted presentation of antigen from IC to CD4⁺ T cells. Considering that also other antigen-presenting cells (APC) (like B cells and macrophages) express FcγR, this could be a possible mechanism of exacerbating/maintaining inflammation in arthritis. Therefore, we sought to explore the role of FcγR and complement in the MHC class II-restricted antigen presentation in vivo and to identify the APC involved in this process.

To gain more insight into the ability of various types of APC to take up and present IC to T cells in vivo, we infused ovalbumin (OVA)-IC into naive mice. Direct ex vivo isolation of the different APC subsets showed that only CD11c⁺ cells, but not macrophages and B cells, are able to (cross-)present efficiently antigen from IC to T cells, although both macrophages and DC are able to capture IC efficiently. Furthermore, depletion of CD11c⁺ cells, using transgenic mice, abrogated the enhanced presentation of antigen in IC, confirming that DC are the predominant APC involved in (cross-)presentation of IC.

To study the contribution of different FcγRs (FcγRI, FcγRII and FcγRIII) in IC-facilitated antigen presentation, we injected OVA-IC in wild-type mice and Fcγ R-knockout mice that have received 3 days earlier CFSE-labeled OVA-specific T cells. Our results indicate that activation of OVA-specific T cells in vivo is 10 times more efficient upon uptake of antibody-complexed OVA than soluble OVA. This effect was absent in mice lacking FcγRI, FcγRII and FcγRIII, but not in complement factor 3 knockout mice, indicating that the enhanced efficiency was FcγR mediated.

Together, these results indicate that the enhanced presentation of antigen in IC and the subsequent activation of T cells in vivo is mediated primarily by DC, not by macrophages or B cells. Therefore, we consider it more likely that the IC-related contribution of macrophages to rheumatoid arthritis is associated with the release of proinflammatory cytokines and molecules upon activation induced by FcγR crosslinking, than to the enhanced activation of autoreactive CD4⁺ T cells. The ability to orchestrate and steer the T-cell responses is the responsibility of DC, further emphasizing the crucial role of DC in controlling (ongoing) T-cell responses.