Epitope specificity plays a critical role in regulating antibody dependent cell mediated cytotoxicity against influenza A virus
Significance In addition to neutralizing antigens, antibodies are also capable of stimulating cellular responses through Fc Fc receptor interactions. The type of response stimulated by these interactions is influenced by both the Fc receptor type expressed on the effector cell and the isotype of antibody to which it is bound. However, how antibody specificity influences Fc receptor functions, and how antibodies of different specificities interact to modulate these functions, remain unknown. Using influenza A virus as a model, we demonstrate that antibody specificity profoundly influences the induction of antibody dependent cell mediated cytotoxicity by effector cells. In addition, we show that interactions among antibodies that bind to discrete epitopes on the same antigen can influence the induction of Fc dependent effector functions. 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.
Proceedings of the National Academy of Sciences