Generation of antigen-specific memory CD4 T cells by heterologous immunization enhances the magnitude of the germinal center response upon influenza infection.

T follicular helper (Tfh) cells are specialized CD4+ T cells that provide help to B cells and are required to form germinal centers within secondary lymphoid organs during an immune response. Germinal centers are necessary for generating high affinity virus-specific antibodies necessary to clear influenza infections, though current vaccines fail to generate long-lived antibodies that universally recognize different influenza strains. We used a "heterologous priming" strategy in mice using a non-influenza viral infection or viral protein subunit vaccination to form memory CD4+ Tfh cells (in previously naïve mice) that can be rapidly recalled into secondary Tfh cells following influenza infection and ideally enhance the germinal center reaction and formation of high affinity antibodies to influenza better than primary Tfh cells. Our study showed that heterologous priming induced an increase in both CD4+ T and B cells early following influenza infection, suggesting we could successfully target enhancement of the germinal center. Despite the enhancement of the early germinal center cellular response, we did not see an increase in influenza-specific antiviral antibodies. Thus, while Tfh cells are critical for the generation of high affinity antibodies, other strategies to target expansion of Tfh cells during influenza vaccination will need to be developed.