title: Hierarchical and Redundant Roles of Activating FcγRs in Protection against Influenza Disease by M2e-Specific IgG1 and IgG2a Antibodies.
abstract: The ectodomain of matrix protein 2 is a universal influenza A virus vaccine candidate that provides protection through antibody-dependent effector mechanisms. Here we compared the functional engagement of Fcγ receptor (FcγR) family members by two M2e-specific monoclonal antibodies (MAbs), MAb 37 (IgG1) and MAb 65 (IgG2a), which recognize a similar epitope in M2e with similar affinities. The binding of MAb 65 to influenza A virus-infected cells triggered all three activating mouse Fcγ receptorsin vitro, whereas MAb 37 activated only FcγRIII. The passive transfer of MAb 37 or MAb 65 in wild-type,Fcer1g-/-,Fcgr3-/-, andFcgr1-/-Fcgr3-/-BALB/c mice revealed the importance of these receptors for protection against influenza A virus challenge, with a clear requirement of FcγRIII for IgG1 MAb 37 being found. We also report that FcγRIV contributes to protection by M2e-specific IgG2a antibodies.IMPORTANCEThere is increased awareness that protection by antibodies directed against viral antigens is also mediated by the Fc domain of these antibodies. These Fc-mediated effector functions are often missed in clinical assays, which are used, for example, to define correlates of protection induced by vaccines. The use of antibodies to prevent and treat infectious diseases is on the rise and has proven to be a promising approach in our battle against newly emerging viral infections. It is now also realized that Fcγ receptors significantly enhance thein vivoprotective effect of broadly neutralizing antibodies directed against the conserved parts of the influenza virus hemagglutinin. We show here that two M2e-specific monoclonal antibodies with close to identical antigen-binding specificities and affinities have a very differentin vivoprotective potential that is controlled by their capacity to interact with activating Fcγ receptors.
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Silvie
authors.initials: S
authors.lastname: Van den Hoecke
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Ehrhardt
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Annasaheb
authors.initials: A
authors.lastname: Kolpe
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Karim
authors.initials: K
authors.lastname: El Bakkouri
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Lei
authors.initials: L
authors.lastname: Deng
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Grootaert
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium.|Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Steve
authors.initials: S
authors.lastname: Schoonooghe
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Anouk
authors.initials: A
authors.lastname: Smet
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Bentahir
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Kenny
authors.initials: K
authors.lastname: Roose
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Michael
authors.initials: M
authors.lastname: Schotsaert
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Schepens
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Nico
authors.initials: N
authors.lastname: Callewaert
authors.affiliation: Department of Biology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Staeheli
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Hengel
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium xavier.saelens@vib-ugent.be.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Saelens
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000914:Antibodies, Viral / Q000276:immunology*; D000915:Antibody Affinity; D000998:Antiviral Agents / Q000494:pharmacology; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D006825:Hybridomas; D007074:Immunoglobulin G / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D017452:Receptors, IgG / Q000502:physiology*; D014763:Viral Matrix Proteins / Q000276:immunology; D000086082:Viroporin Proteins
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000998:Antiviral Agents; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D017452:Receptors, IgG; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
keywords: Fcγ receptors; IgG antibody isotype; M2e; influenza A virus; mechanism of protection; viral infection