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.
Highlights
The elderly population is susceptible to novel infections, especially the annual, seasonal epidemics caused by influenza A viruses [1,2], with increased occurrence, severity of infection and reduced vaccine efficacy being attributed to agerelated decline in immune capacity [3,4,5,6]
We found that influenza-specific T cell responses are compromised in the aged mice, vaccination with influenza early in life ‘locks’ optimal T-cell responsiveness, maintains functional quality, persistence of preferred clones and a characteristic T cell hierarchy
As a main question of the present study, we asked whether any age-related compromise of CD8+ T cell function and diversity might be modified by priming early or late i.p. with 1.56107 pfu of the serologically distinct PR8 (H1N1) virus that has the same immunogenic CD8+ T cell peptides as HK
Summary
The elderly population is susceptible to novel infections, especially the annual, seasonal epidemics caused by influenza A viruses [1,2], with increased occurrence, severity of infection and reduced vaccine efficacy being attributed to agerelated decline in immune capacity [3,4,5,6]. Ageing can be associated with abnormal cellular functions such as distorted cytokine secretion (IL-2, IL-4 and IFN-c) profiles [15,16,17], decreased granzyme B production [18,19] and reduced proliferative capacity due to the loss of CD28 expression [20]. Naıve T cell attrition has been inferred from observed reductions in the diversity of antigen-specific TCR repertoires in aged mice [5,22]. The findings so far suggest that the capacity to respond effectively to new influenza infections in aged mice requires the maintenance of a diverse pool of functional peripheral T cells. The importance of long-lived, antigen-specific memory CD8+ T cells capable of rapid recall following the secondary infection has been well documented for the respiratory viruses in mice [27,28] and Author Summary
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