Interferon-γ receptor signaling is critical for balanced immune activation and protection against influenza after vaccination.

To better understand the contribution of interferon-γ (IFN-γ) receptor signaling to vaccine-induced immunity, we employed A129 (IFN-α/β receptor-deficient) and AG129 (IFN-α/β/γ receptor-deficient) mouse models. AG129 mice induced comparable levels of virus-specific IgG after vaccination with influenza virus H5 hemagglutinin (HA) virus-like particles (VLPs). Vaccinated AG129 mice with HA VLPs exhibited impaired Th1-immune responses, lower hemagglutination inhibition (HAI) titers, increased susceptibility to virus infection, and lower survival rates following influenza virus (H5N1) challenge than vaccinated A129 mice. The AG129 mice also displayed defective germinal center and plasma cell responses, dysregulated lung inflammation with elevated pro-inflammatory cytokines and chemokines, impaired recruitment of monocytes, natural killer cells, and antigen-presenting cells after HA VLP vaccination and virus challenge, compared to A129 mice. Collectively, these findings underscore the critical role of IFN-γ signaling in coordinating effective and balanced immune responses to influenza HA VLP vaccination and conferring protection against virus infection.