title: Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus.
abstract: The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising "universal" influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo. However, the way in which Fc-dependent effector functions are regulated by polyclonal influenza virus-binding antibody mixtures in vivo has never been defined. Here, we demonstrate that interactions among viral glycoprotein-binding antibodies of varying specificities regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We show that the mechanism responsible for this phenotype relies upon competition for binding to HA on the surface of infected cells and virus particles. Nonneutralizing antibodies were poor inducers and did not inhibit antibody-dependent cell-mediated cytotoxicity. Interestingly, anti-neuraminidase antibodies weakly induced antibody-dependent cell-mediated cytotoxicity and enhanced induction in the presence of HA stalk-binding antibodies in an additive manner. Our data demonstrate that antibody specificity plays an important role in the regulation of ADCC, and that cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Wenqian
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Gene S
authors.initials: GS
authors.lastname: Tan
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Mullarkey
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Institute of Infectious Diseases Research, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada L8S 4L8.
authors.forename: Mannie Man Wai
authors.initials: MM
authors.lastname: Lam
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Florian
authors.initials: F
authors.lastname: Krammer
authors.affiliation: Section of Rheumatology, Department of Medicine, The Knapp Center for Lupus and Immunology Research, Committee on Immunology, The University of Chicago, Chicago, IL 60637.
authors.forename: Carole
authors.initials: C
authors.lastname: Henry
authors.affiliation: Section of Rheumatology, Department of Medicine, The Knapp Center for Lupus and Immunology Research, Committee on Immunology, The University of Chicago, Chicago, IL 60637.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Ashkar
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Institute of Infectious Diseases Research, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada L8S 4L8; mmiller@mcmaster.ca.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Miller
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D000915:Antibody Affinity / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D001667:Binding, Competitive; D015415:Biomarkers; D002460:Cell Line; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011961:Receptors, Fc / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D015415:Biomarkers; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011961:Receptors, Fc
keywords: ADCC; Fc receptor; NK cell; antibody; influenza virus