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.

Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8 + T cells in aged mice

“…Primary IAV infection of young adult mice results in a well-characterized CD8 + T-cell immunodominance hierarchy, which shifts significantly during aging (13,22). To establish when this shift occurs, we tracked CD8 + T-cell responses to four IAV-derived epitopes following infection: D b NP 366 and D b PA 224 (immunodominant), and K b PB1 703 and D b PB1-F2 62 (subdominant), at 3, 12, and 18 mo.…”

“…The age-related decline in naïve epitope-specific CTLps may occur stochastically, leading to an equivalent rate of loss across all epitope specificities or could reflect the differential fitness of particular CTLp sets in an aged environment. Earlier experiments demonstrated that the IAV-specific immunodominance hierarchy shifts in B6 mice, with infection of aged naïve mice resulting in substantial loss of the immunodominant D b NP 366 -specific CD8 T-cell response, a maintenance of the prominent D b PA 224 -specific response, and a relative increase in the subdominant K b PB1 703 -and D b PB1-F2 62 -specific responses (13,22). A previous study also indirectly suggested that age-related "holes" emerge in the naïve CTLp TCR repertoire, particularly for those epitope-specific sets with lower precursor frequencies (13).…”

“…Primary responses to the D b NP 366-374 and D b PA 224-233 epitopes (derived from nucleoprotein and acid polymerase proteins, respectively) are immunodominant in young adult mice, whereas those to a polymerase B subunit 1 epitope (K b PB1 [703][704][705][706][707][708][709][710][711] ) and an epitope derived from a shifted reading frame of PB1 (D b PB1-F2 62-70 ) are subdominant (21). This numerical immunodominance hierarchy shifts with aging, with a decrease in D b NP 366 -specific responses alongside an increase in K b PB1 703 -and D b PB1-F2 62 -specific responses (13,22). It has been suggested that this reflects the stochastic decay of CTLp (13), but…”

Reduced naïve CD 8 + T ‐cell priming efficacy in elderly adults

“…Indeed, contraction of the murine naïve T‐cell repertoire can impair T‐cell responses to immunodominant epitopes (Yager et al ., 2008; Valkenburg et al ., 2012). Intrinsic age‐related defects in naïve T‐cell responsiveness linked to gene expression profiles and cytokine secretion have also been documented in old mice (Mirza et al ., 2011; Decman et al ., 2012; Jiang et al ., 2013).…”

Establishment of functional influenza virus-specific CD8+ T cell memory pools after intramuscular immunization

“…In addition, DCs act as antigen-presenting cells for the efficient priming of T cells recognising endogenously-processed viral peptides. CTLs induced in this way are characterised by memory responses lasting the lifetime of the mouse [18]. Although not a suitable route for human vaccination, examination of the responses induced via this non-productive provide insight into the requirements for establishing successful vaccine-induced broadly cross-reactive memory CTLs.…”