Naïve T cells surpass pre-existing memory to dominate post-vaccine responses in humans

Abstract

Abstract Background There is a critical unmet need for vaccines against emerging diseases and common infections, such as HIV, malaria, and tuberculosis. Defining the mechanisms by which memory T cell responses are generated in humans is essential for developing efficacious vaccines. We have previously described that human adults possess pre-existing memory phenotype CD4+ T cells specific for viral antigens to which they have never been expose. The goal of our study is to test how memory precursors respond to antigen challenge and to identify other key aspects of the human precursor repertoire that are required for a robust vaccine response. Methods We are using yellow fever virus (YFV) vaccination as a model to examine the link between precursor T cell composition and cellular response to cognate antigen stimulation. We screened study participants for HLA allele of interest and the absence of prior exposure to YFV by serology. We then use peptide-MHC tetramers to identify YFV-specific T cells before vaccination and at multiple time points after YFV vaccination. Results Direct ex vivo analyses of YFV-specific CD4+ T cells in the blood revealed three key observations. First, precursor T cells vary in size, but a larger precursor frequency does not predict better post-vaccination response. Second, naïve precursors outcompete memory precursors to generate a larger effector population. Third, the magnitude of effector cell frequency predicts clonotypic selection into the stable memory pool. Conclusions Durable memory response to primary immune challenge is dependent on successful preservation of naïve T cell repertoire. Age-associated erosion of naïve T cell pool may contribute to the decreased effectiveness of vaccines in older individuals.