Cross-presentation of IgG-containing immune complexes (ICs) is an important means by which dendritic cells (DCs) activate CD8+T cells, yet it proceeds by an incompletely understood mechanism. We show that monocyte-derived CD8-CD11b+DCs require the neonatal Fc receptor for IgG (FcRn) to conduct cross-presentation of IgG ICs. Consequently, in the absence of FcRn, Fcγ receptor (FcγR)-mediated antigen uptake fails to initiate cross-presentation. FcRn is shown to regulate the intracellular sorting of IgG ICs to the proper destination for such cross-presentation to occur. We demonstrate that FcRn traps antigen and protects it from degradation within an acidic loading compartment in association with the rapid recruitment of key components of the phagosome-to-cytosol crosspresentation machinery. This unique mechanism thus enables cross-presentation to evolve from an atypically acidic loading compartment. FcRn-driven cross-presentation is further shown to control cross-priming of CD8+T-cell responses in vivo such that during chronic inflammation, FcRn deficiency results in inadequate induction of CD8+T cells. These studies thus demonstrate that crosspresentation in CD8-CD11b+DCs requires a two-step mechanism that involves FcγR-mediated internalization and FcRn-directed intracellular sorting of IgGICs. Given the centrality of FcRn in controlling cross-presentation, these studies lay the foundation for a unique means to therapeutically manipulate CD8+T-cell responses.

doi.org/10.1073/pnas.1019037108, hdl.handle.net/1765/33399
Proceedings of the National Academy of Sciences of the United States of America
Erasmus MC: University Medical Center Rotterdam

Baker, K, Qiao, S-W, Kuo, T.T, Aveson, V.G, Platzer, B, Andersen, J.-T, … Blumberg, R.S. (2011). Neonatal Fc receptor for IgG (FcRn) regulates cross-presentation of IgG immune complexes by CD8-CD11b+ dendritic cells. Proceedings of the National Academy of Sciences of the United States of America, 108(24), 9927–9932. doi:10.1073/pnas.1019037108