Early Priming Minimizes the Age-Related Immune Compromise of CD8 ⁺ T Cell Diversity and Function

Abstract

The elderly are particularly susceptible to influenza A virus infections, with increased occurrence, disease severity and reduced vaccine efficacy attributed to declining immunity. Experimentally, the age-dependent decline in influenza-specific CD8 ⁺ T cell responsiveness reflects both functional compromise and the emergence of ‘repertoire holes’ arising from the loss of low frequency clonotypes. In this study, we asked whether early priming limits the time-related attrition of immune competence. Though primary responses in aged mice were compromised, animals vaccinated at 6 weeks then challenged >20 months later had T-cell responses that were normal in magnitude. Both functional quality and the persistence of ‘preferred’ TCR clonotypes that expand in a characteristic immunodominance hierarchy were maintained following early priming. Similar to the early priming, vaccination at 22 months followed by challenge retained a response magnitude equivalent to young mice. However, late priming resulted in reduced TCRβ diversity in comparison with vaccination earlier in life. Thus, early priming was critical to maintaining individual and population-wide TCRβ diversity. In summary, early exposure leads to the long-term maintenance of memory T cells and thus preserves optimal, influenza-specific CD8 ⁺ T-cell responsiveness and protects against the age-related attrition of naïve T-cell precursors. Our study supports development of vaccines that prime CD8 ⁺ T-cells early in life to elicit the broadest possible spectrum of CD8 ⁺ T-cell memory and preserve the magnitude, functionality and TCR usage of responding populations. In addition, our study provides the most comprehensive analysis of the aged (primary, secondary primed-early and secondary primed-late) TCR repertoires published to date.

Author Summary

The elderly population is particularly susceptible to novel infections, especially the annual, seasonal epidemics caused by influenza viruses. Established T cell immunity directed at conserved viral regions provides some protection against influenza infection and promotes more rapid recovery, thus leading to better clinical outcomes. We asked whether priming early in life limits the time-related attrition of immune competence. We found that although influenza-specific T cell responses are compromised in the aged mice, vaccination with influenza early (but not late) in life ‘locks’ optimal T-cell responsiveness, maintains functional quality, persistence of preferred clones and a characteristic T cell hierarchy. Overall, our study supports development of vaccines that prime T cells early in life to elicit the broadest possible spectrum of pre-existing T cell memory and preserve the magnitude, functionality and clonal usage of responding populations for life-long immunity against influenza viruses.