Naive phenotype antigen-specific CD4 +T cells persist in the memory repertoire after vaccination

Abstract Immunization leads to activation and differentiation of antigen-specific T cells, resulting in the development of immunological memory. However, how the human immune repertoire changes after vaccination remains incompletely understood. Here, we used the live attenuated yellow fever virus (YFV) vaccine or the SARS-CoV-2 mRNA vaccine as models to track post-vaccine kinetics in healthy donors. We quantified and characterized 36 distinct YFV-specific T cell populations and 25 SARS-CoV-2-specific populations by direct ex vivo peptide-MHC tetramer staining. Unexpectedly, we found naïve-phenotype vaccine-specific T cells reappearing after vaccination. On average, 20% of T cells retained a naive phenotype by CD45RO and CCR7 staining although each population had previously expanded after vaccination. A subset of naïve-like T cells expressed other differentiation markers consistent with T memory stem cells (TSCM), but some naïve-like T cells were negative for all memory markers tested. These naïve-phenotype T cells were able to respond to antigens and showed an increased expression of a recent thymic immigrant marker CD31. In conclusion, our results provided the surprising finding that the post-exposure T cell repertoire contains naïve antigen-specific T cells. We plan to test the possibility that the thymus continues to add new T cells into the adult immune repertoire in future experiments. NIH (R01 AI134879) NIH (R01 AO66358)