Vaccination reshapes the virus-specific T cell repertoire in unexposed adults

We examined how baseline CD4+ T cell repertoire and precursor states impact responses to pathogen infection in humans using primary immunization with yellow fever virus (YFV) vaccine. YFV-specific T cells in unexposed individuals were identified by peptide-MHC tetramer staining and tracked pre- and post-vaccination by tetramers and TCR sequencing. A substantial number of YFV-reactive T cells expressed memory phenotype markers and contained expanded clones in the absence of exposure to YFV. After vaccination, pre-existing YFV-specific T cell populations with low clonal diversity underwent limited expansion, but rare populations with a reservoir of unexpanded TCRs generated robust responses. These altered dynamics reorganized the immunodominance hierarchy and resulted in an overall increase in higher avidity T cells. Thus, instead of further increasing the representation of dominant clones, YFV vaccination recruits rare and more responsive T cells. Our findings illustrate the impact of vaccines in prioritizing T cell responses and reveal repertoire reorganization as a key component of effective vaccination. [Display omitted] •Class II tetramer enrichment identifies YFV-reactive T cells in unexposed adults•CD4+ T cell precursor states predict post-vaccine dynamics•Single-cell TCR sequencing reveals reorganization of clonal hierarchy by vaccination•Repertoire diversity facilitates robust peripheral T cell selection Pan et al. examine how baseline CD4+ T cell repertoire and precursor states impact responses to pathogen infection in humans using primary immunization with yellow fever virus (YFV) vaccine. They find that instead of increasing the representation of dominant pre-existing YFV-reactive clones, vaccination reorganizes the immunodominance hierarchy by recruiting rare and more responsive T cells.