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

Abstract

We examined how baseline CD4+ Tcell repertoire and precursor states impact responses to pathogen infection in humans using primary immunization with yellow fever virus (YFV) vaccine. YFV-specific Tcells 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 Tcells expressed memory phenotype markers and contained expanded clones in the absence of exposure to YFV. After vaccination, pre-existing YFV-specific Tcell 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 Tcells. Thus, instead of further increasing the representation of dominant clones, YFV vaccination recruits rare and more responsive Tcells. Our findings illustrate the impact of vaccines in prioritizing Tcell responses and reveal repertoire reorganization as a key component of effective vaccination.