The Neonatal FcR-Mediated Presentation of Immune-Complexed Antigen Is Associated with Endosomal and Phagosomal pH and Antigen Stability in Macrophages and Dendritic Cells

Abstract

The FcγRs found on macrophages (Mϕs) and dendritic cells (DCs) efficiently facilitate the presentation or cross-presentation of immune-complexed Ags to T cells. We found that the MHC class I-related neonatal FcR for IgG (FcRn) in both Mϕs and DCs failed to have a strong effect on the cross-presentation of immune complex (IC) OVA Ag to CD8+ T cells. Interestingly, endosomal FcRn enhanced the presentation of the monomeric OVA-IC to CD4+ T cells robustly, whereas FcRn in phagosomes exerted distinctive effects on Ag presentation between Mϕs and DCs. The presentation of phagocytosed OVA-ICs to CD4+ T cells was considerably enhanced on wild-type versus FcRn-deficient Mϕs, but was not affected in FcRn-deficient DCs. This functional discrepancy was associated with the dependence of IgG–FcRn binding in an acidic pH. Following phagocytosis, the phagosomal pH dropped rapidly to <6.5 in Mϕs but remained in the neutral range in DCs. This disparity in pH determined the rate of degradation of phagocytosed ICs. Thus, our findings reveal that FcRn expression has a different effect on Ag processing and presentation of ICs to CD4+ T cells in the endosomal versus phagosomal compartments of Mϕs versus DCs.

A Neonatal Fc Receptor-Targeted Mucosal Vaccine Strategy Effectively Induces HIV-1 Antigen-Specific Immunity to Genital Infection

“…From this study, we deduce that an FcRn-targeted HIV subunit vaccine delivers soluble antigens to mucosal DCs and gives rise to long-lived T cell help for antibody responses (5,25,46). FcRn-targeted mucosal immunizations may be further benefited by an additional function for FcRn in antigen presentation (29,32,40). Additional studies are required to study memory and secondary responses after the targeted delivery of antigens to DCs via FcRn-mediated transport.…”

Intranasal Administration of Antibody-Bound Respiratory Syncytial Virus Particles Efficiently Primes Virus-Specific Immune Responses in Mice

“…However, a different explanation might be that there was a difference in the antigen-presenting cell populations involved in the processes described in the different studies. A recent publication showed that FcRn exclusively facilitated processing of multimeric Ig-complexed OVA in macrophages and not in DCs (46). Apparently, the phagosomes in DCs did not reach the low pH required for IgG binding to FcRn, while in macrophages the pH rapidly dropped to Ͻ6.5, allowing FcRn binding.…”

“…Monovalent internalization of IgG-OVA was, however, FcRn dependent in both DCs and macrophages. Thus, FcRnindependent IC-RSV antigen presentation might be simply due to different mechanisms of uptake and presentation (phagocytosis versus endocytosis), or as described by Liu et al (46) due to the neutral pH in the phagosomes of some types of DCs. In our studies, it might be possible that lung DCs efficiently captured IC-RSV via Fc␥R but did not (efficiently) process them and only transported captured viral material to the draining lymph nodes.…”

NFκB induces overexpression of bovine FcRn

“…[16][17][18][19] We previously reported the effects of FcRn overexpression accomplished by Tg modification in mice and rabbits. [20][21][22][23][24][25] These effects include quantitative as well as qualitative augmentation in the humoral immune response of these animals.…”