Antibody idiotype plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity (ADCC) 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. Recently, elicitation of broadly-neutralizing antibodies which target the conserved hemagglutinin stalk domain have emerged as a promising “universal” influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions, such as antibody-dependent cell-mediated cytotoxicity, 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-binding antibody idiotypes in vivo has never been defined. Here, we demonstrate that complex interactions among viral glycoprotein-binding antibody idiotypes regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We propose that antibody idiotype serves as a critical determinant in the activation of ADCC. This is the first demonstration that cross-talk among antibody idiotypes is important for the regulation of Fc-dependent effector functions. This phenomenon will have major implications for not only the development of universal influenza virus vaccines, but also in any scenario wherein Fc-dependent effector functions are engaged in the context of polyclonal responses containing multiple antibody idiotypes.