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Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11931-11936. Epub 2016 Oct 3.

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus.

Author information

1
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
2
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
3
Department of Biochemistry and Biomedical Sciences, Institute of Infectious Diseases Research, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada L8S 4L8.
4
Section of Rheumatology, Department of Medicine, The Knapp Center for Lupus and Immunology Research, Committee on Immunology, The University of Chicago, Chicago, IL 60637.
5
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.
6
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.

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.

KEYWORDS:

ADCC; Fc receptor; NK cell; antibody; influenza virus

PMID:
27698132
PMCID:
PMC5081650
DOI:
10.1073/pnas.1609316113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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