Distinct and complementary roles of CD4 T cells in protective immunity to influenza virus

•Humans have a diverse repertoire of circulating CD4 T cells specific for influenza viral proteins.•Critical CD4 T cell functions include help for B cell and CD8 T cell responses and cytotoxicity.•Although follicular helper cells and cytotoxic CD4 T cells are critical, their differentiation is reciprocally regulated.•Universal influenza vaccines should be designed overcome deficits in CD4 T cell function and specificity. CD4 T cells play a multiplicity of roles in protective immunity to influenza. Included in these functions are help for high affinity antibody production, enhancement of CD8 T cell expansion, function and memory, acceleration of the early innate response to infection and direct cytotoxicity. The influenza-specific CD4 T cell repertoire in humans established through exposures to infection and vaccination has been found to be highly variable in abundance, specificity and functionality. Deficits in particular subsets of CD4 T cells recruited into the response result in diminished antibody responses and protection from infection. Therefore, improved strategies for vaccination should include better methods to identify deficiencies in the circulating CD4 T cell repertoire, and vaccine constructs that increase the representation of CD4 T cells of the correct specificity and functionality.