The detailed and unbiased characterization of HA-reactive memory and naive CD4+ T cell repertoires, paralleled by a deep analysis of the naturally presented repertoire of MHC-II–binding HA peptides by mass spectrometry (MS)–based immunopeptidomics, allowed us to shed new light on the factors governing CD4+ T cell clonal selection and immunodominance to influenza HA in humans. This evidence concerns the gene CD4 and influenza.