TFH cells are a helper subset to localize in B cell follicle and germinal center (GC) of second lymphoid organ and to control B cell response that largely rely on TFH secreted cytokines, IL-4 and IL-21. We recently identified IFN-γ dependent antibody, IgG2 antibodies predominate in the response to vaccination with inactivated Influenza A virus (IAV) and were responsible for protective immunity to lethal challenge with pathogenic H5N1 and pandemic H1N1 IAVs. The IgG2 antibody responsible for protective immunity was independent on germinal center (GC) and TFH based on the evidences that B or T cell-specific ablation of the Bcl6 did not have an impact on IgG2 responses specific for HA antigen. We identified that IL-21 and IFN-γ secreted from CXCR3+CXCR5- TH1 cells accounted for the low affinity of virus specific IgG2 protective antibodies. The affinity of IgG2 from Bcl6-deficient mice against HA was relatively low, indicating that high-affinity antibodies are not entirely necessary for protective IgG2 responses in systemic vaccination.
The mucosal IgA antibody specific for HA in the lung has a potential to cross-react with other strains of influenza virus (breadth). We found that virus replication was needed to induce protective and cross-reactive IgA antibody. The production of neutralizing IgA antibodies associated with lung residential CD4 T cells that expressed CD103, CXCR3 and IFN-γ, and with IL-6 dependent B cell activation. These results indicated that flu replication promoted unique lung environment to confer cross-reactive neutralization in IgA antibodies. Therefore, induction of IgG2 antibody in systemic vaccination and IgA response in the lung by live flu administration should be promising strategies to induce effective neutralizing antibodies to combat emerging pandemic influenza viruses.