Central memory T cells with key TCR repertoires and gene expression profiles dominate influenza CD8+ T cell pools across the human lifespan

Abstract

Central memory CD8 + T cells (T cm ) represent the prominent memory T cell subset in human blood, yet the persistence of T cell receptor (TCR) clonotypic and transcriptional features of epitope-specific T cm pools across the human lifespan remains unknown. We analyzed T cm CD8 + T cells specific for HLA-A*02:01-M1 58–66 (A2/M1 58 ; a prominent influenza epitope) in newborns, children, adults, and older adults directly ex vivo. Our data provide evidence that epitope-specific T cm CD8 + pools dominate influenza-specific memory A2/M1 58 + CD8 + T cell responses from the early childhood until old age. T cm gene signatures were largely maintained across the age groups, although self-renewal genes defined T cm pools in children, while older adult T cm A2/M1 58 + CD8 + T cells displayed detoxication and stress profiles. TCRαβ diversity within T cm A2/M1 58 + CD8 + T cell pools was greater in children and older adults, when compared to adults. The key public-associated TCRαβ clonotypes largely persisted across the human lifespan, although their highest frequency was detected in adults, reflecting lower TCRαβ diversity in this group. Older adults displayed increased TCRαβ heterogeneity, underpinned by large TCRαβ clonotype expansions of private TCRαβ clonotypes. Our study highlights the importance of largely preserved virus-specific T cm pools across the human lifespan and advocates for boosting persistent TCRαβ clonotypes within this key peripheral blood subset.