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.
Highlights
The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections
Because monoclonal bnAbs that bind to the HA stalk domain have been reported to potently induce antibody-dependent cell-mediated cytotoxicity (ADCC), whereas mAbs to the HA head domain do not, we sought to investigate how ADCC would be regulated in the context of a polyclonal response, to better recapitulate in vivo conditions [20]
We first made use of primary human natural killer (NK) cells freshly isolated from the peripheral blood of healthy donors
Summary
The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. 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. In addition to virus neutralization, recent work by DiLillo et al [20] has demonstrated that HA stalk-binding antibodies are potent inducers of antibody-dependent cell-mediated cytotoxicity (ADCC), and that this property is essential for optimal protection in vivo. These authors reported that strain-specific HAI+ antibodies, which bind to the head domain of HA, do not elicit ADCC [20]. We show that interactions among antibodies that bind to discrete epitopes on the same antigen can influence the induction of Fc-dependent effector functions
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