Gradual changes within long-lived influenza virus-specific CD8+ T cells are associated with the loss of public TCR clonotypes in older adults

Abstract

Background: Susceptibility to life-threatening influenza increases with age, partly due to declining immunity. Frequency, phenotype and T-cell receptor (TCR) composition of influenza-specific CD8⁺ T-cells directed at the prominent A2/M158 influenza epitope change across the human lifespan. Methods: We investigated longevity and mechanisms underlying age-related changes in influenza-specific TCR repertoires by performing longitudinal analyses in young and older adults across 7–12 years within A2/M158⁺CD8⁺ T-cells using peptide-HLA tetramers directly ex vivo. Paired TCRαβ-chains were used to track clonotypes over time within individuals. Findings: Expanded public and private TCR clonotypes were long-lived but gradually declined over time. Loss of public clonotypes was initially compensated by expansions of clonotypes expressing public-associated features. Once these public-associated TCR clonotypes were abated in older adults, the void was filled by expansions of less similar private TCR clonotypes. Expanded older private TCR clonotypes also declined over time and were gradually replaced by other private TCR clonotypes with low similarity to public TCR clonotypes detected in adults. Interpretation: Despite our relatively small cohort, we provided conclusive evidence that CD8⁺ T-cells to a single HLA-A2-restricted influenza-epitope are long-lived. However, dynamic changes occur at the clonotypic level, which eventually result in loss of public clonotypes, indicating that T-cell-based influenza vaccines are likely more effective in adults than older adults. Funding: This research was supported by the National Health and Medical Research Council ( #1173871, #1159272), the Australian Research Council ( #190102704), European Union's Horizon 2020 ( #792532), the University of Melbourne. Funders had no role in design, analysis or reporting of the study.