Through tetramer staining, Pan and Aiamkitsumrit et al. traced yellow fever virus (YFV)-specific CD4+ T cells in healthy, YFV-unexposed patients before and after YFV vaccination. YFV-specific T cells were detected prior to immunization and were heterogeneous in abundance, memory marker expression, and proliferation following vaccination. Although vaccination increased overall YFV-specific T cell frequency, TCR affinity, and clonotype diversity, the expansion of YFV-specific CD4+ T cell populations inversely correlated with their pre-vaccine frequencies; initially rare YFV-specific T cell populations selectively expanded, shifting the clonal repertoire.
Contributed by Alex Najibi
ABSTRACT: 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.