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

## TL;DR

The study finds that central memory CD8+ T cells with specific TCRs and gene expression patterns persist across the human lifespan in response to influenza.

## Contribution

The study reveals that key TCR repertoires and gene expression profiles of influenza-specific central memory CD8+ T cells remain largely preserved across different age groups.

## Key findings

- Central memory CD8+ T cells specific for the influenza epitope A2/M158 persist across the human lifespan.
- Key TCRαβ clonotypes are maintained in central memory CD8+ T cell pools despite age-related changes in diversity.
- Older adults show increased TCRαβ heterogeneity driven by private clonotype expansions.

## Abstract

Central memory CD8+ T cells are important in providing protection against viral infections, including influenza. However, it is not well understood how the transcriptomic features and T cell receptor (TCR) repertoires of influenza-specific central memory CD8+ T cells change across the human lifespan. We studied central memory CD8+ T cells specific for the prominent and conserved influenza A derived HLA-A*02:01-restricted M158–66 peptide (A2/M158). We show that gene signatures of central memory A2/M158+ CD8+ T cells are largely similar across the human lifespan and key TCRs are maintained within the central memory A2/M158+ CD8+ pools. Our study highlights persistence of the central memory CD8+ T cell subset across the human lifespan and advocates for boosting persistent TCRs within this subset.

Central memory CD8+ T cells (Tcm) 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 Tcm pools across the human lifespan remains unknown. We analyzed Tcm CD8+ T cells specific for HLA-A*02:01-M158–66 (A2/M158; a prominent influenza epitope) in newborns, children, adults, and older adults directly ex vivo. Our data provide evidence that epitope-specific Tcm CD8+ pools dominate influenza-specific memory A2/M158+CD8+ T cell responses from the early childhood until old age. Tcm gene signatures were largely maintained across the age groups, although self-renewal genes defined Tcm pools in children, while older adult Tcm A2/M158+CD8+ T cells displayed detoxication and stress profiles. TCRαβ diversity within Tcm A2/M158+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 Tcm pools across the human lifespan and advocates for boosting persistent TCRαβ clonotypes within this key peripheral blood subset.