Influenza A virus is a significant cause of morbidity and mortality worldwide, particularly among young children and the elderly. Current
vaccines induce
neutralizing antibody responses directed toward highly variable viral
surface proteins, resulting in limited heterosubtypic protection to new viral serotypes. By contrast, memory CD4 T cells recognize conserved
viral proteins and are cross-reactive to multiple
influenza strains. In humans, virus-specific memory CD4 T cells were found to be the protective correlate in
human influenza challenge studies, suggesting their key role in protective immunity. In mouse models, memory CD4 T cells can mediate protective responses to secondary
influenza infection independent of B cells or CD8 T cells, and can influence innate immune responses. Importantly, a newly defined, tissue-resident CD4 memory population has been demonstrated to be retained in lung tissue and promote optimal protective responses to an
influenza infection. Here, we review the current state of results regarding the generation of memory CD4 T cells following primary
influenza infection, mechanisms for their enhanced efficacy in protection from secondary challenge including their phenotype, localization, and function in the context of both mouse models and human
infection. We also discuss the generation of memory CD4 T cells in response to
influenza vaccines and its future implications for vaccinology.