title: Neonatal Fc receptor for IgG (FcRn) regulates cross-presentation of IgG immune complexes by CD8-CD11b+ dendritic cells.
abstract: 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 cross-presentation 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 cross-presentation in CD8(-)CD11b(+) DCs requires a two-step mechanism that involves FcγR-mediated internalization and FcRn-directed intracellular sorting of IgG ICs. 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.
authors.affiliation: Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Kristi
authors.initials: K
authors.lastname: Baker
authors.forename: Shuo-Wang
authors.initials: SW
authors.lastname: Qiao
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Kuo
authors.forename: Victoria G
authors.initials: VG
authors.lastname: Aveson
authors.forename: Barbara
authors.initials: B
authors.lastname: Platzer
authors.forename: Jan-Terje
authors.initials: JT
authors.lastname: Andersen
authors.forename: Inger
authors.initials: I
authors.lastname: Sandlie
authors.forename: Zhangguo
authors.initials: Z
authors.lastname: Chen
authors.forename: Colin
authors.initials: C
authors.lastname: de Haar
authors.forename: Wayne I
authors.initials: WI
authors.lastname: Lencer
authors.forename: Edda
authors.initials: E
authors.lastname: Fiebiger
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015153:Blotting, Western; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D045142:Cross-Priming / Q000276:immunology*; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D016264:Dextran Sulfate; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000276:immunology / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000276:immunology / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: D000941:Antigens; D039481:CD11b Antigen; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D011961:Receptors, Fc; D017452:Receptors, IgG; D000075745:rab27 GTP-Binding Proteins; D016264:Dextran Sulfate; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D025262:Vacuolar Proton-Translocating ATPases; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins; C100688:Fc receptor, neonatal