We observed that infl uenza-specifi c CD4-effector T cells could be generated by long-term cultures in vitro and easily monitored by fl ow cytometry as IFN-γ-producing cells. When this approach was used, a small frequency of CD4 T cells specifi c for H5N1 subtype could be detected in several persons at baseline. Seasonal vaccine administration may enhance the frequency of reactive CD4 T cells, boosting the cross-subtype cellular immunity against avian infl uenza (H5N1). We also observed that seasonal vaccination raised neutralizing immunity against H5N1 subtype in a large number of donors, showing the existence of an antibody-dependent cross-type immunity. Thus, cross-reactive immunity may involve cellular and/or humoral responses, but the humoral response seems to be CD4 independent.