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Early priming minimizes the age-related immune compromise of CD8⁺ T cell diversity and function.

Valkenburg SA, Venturi V, Dang TH, Bird NL, Doherty PC, Turner SJ, Davenport MP, Kedzierska K - PLoS Pathog. (2012)

Bottom Line: However, late priming resulted in reduced TCRβ diversity in comparison with vaccination earlier in life.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Melbourne, Parkville, Melbourne, Australia.

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.

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Immunodominance hierarchies in aged mice after 10 infection or 20 challenge of primed-early mice.The relative prevalence of the immunodominant DbNP366+CD8+ and DbPA224+CD8+ T cell population over the subdominant DbPB1703+CD8+ and KbPB1-F262+CD8+ sets. Results are shown for (A, B) 10 and (C, D) 20 HK infection in (A, C) young and (B, D) aged mice. The relative contributions of particular antigen-specific CD8+ T cells were analysed based on total cell responses (Figure 1 for DbNP366+CD8+ and DbPA224+CD8+ and data not shown for DbPB1703+CD8+ and KbPB1-F262+CD8+). Data represent the mean proportion of a particular peptide-specific CD8+ population. * = p<0.01 shows a difference between young and aged animals. Experimental outline as in Figure 1AB.
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ppat-1002544-g002: Immunodominance hierarchies in aged mice after 10 infection or 20 challenge of primed-early mice.The relative prevalence of the immunodominant DbNP366+CD8+ and DbPA224+CD8+ T cell population over the subdominant DbPB1703+CD8+ and KbPB1-F262+CD8+ sets. Results are shown for (A, B) 10 and (C, D) 20 HK infection in (A, C) young and (B, D) aged mice. The relative contributions of particular antigen-specific CD8+ T cells were analysed based on total cell responses (Figure 1 for DbNP366+CD8+ and DbPA224+CD8+ and data not shown for DbPB1703+CD8+ and KbPB1-F262+CD8+). Data represent the mean proportion of a particular peptide-specific CD8+ population. * = p<0.01 shows a difference between young and aged animals. Experimental outline as in Figure 1AB.

Mentions: The beneficial effect of the early CD8+ priming on the immunodominant low-precursor responses like the DbNP366-specific population following influenza infection at the extreme age was most striking when the relative contributions of particular antigen-specific CD8+ T cells were analysed based on total cell numbers (Figure 2, calculations based on Figure 1 for immunodominant DbNP366+CD8+ and DbPA224+CD8+ pools, and data not shown for subdominant DbPB1703+CD8+ and KbPB1-F262+CD8+ populations). In the aged mice, the primary CD8+ T cell responses showed a shift in the typical immunodominance hierarchy (Figure 2B), with the contribution of the immunodominant DbNP366+CD8+ population being significantly lower in the aged mice (9.4±3.6%) in comparison to young animals (43.4±15%; p<0.01; Figure 2A). The differential immunodominance hierarchy resulted mainly from significantly increased contribution of KbPB1703+CD8+ T cells (Figure 2). This led to major modifications in response hierarchy following primary influenza virus infection of aged mice KbPB1703>DbPA224>DbPB1-F262>DbNP366, with the comparable profile for young mice being DbNP366>DbPA224 = KbPB1703≫DbPB1-F262.


Early priming minimizes the age-related immune compromise of CD8⁺ T cell diversity and function.

Valkenburg SA, Venturi V, Dang TH, Bird NL, Doherty PC, Turner SJ, Davenport MP, Kedzierska K - PLoS Pathog. (2012)

Immunodominance hierarchies in aged mice after 10 infection or 20 challenge of primed-early mice.The relative prevalence of the immunodominant DbNP366+CD8+ and DbPA224+CD8+ T cell population over the subdominant DbPB1703+CD8+ and KbPB1-F262+CD8+ sets. Results are shown for (A, B) 10 and (C, D) 20 HK infection in (A, C) young and (B, D) aged mice. The relative contributions of particular antigen-specific CD8+ T cells were analysed based on total cell responses (Figure 1 for DbNP366+CD8+ and DbPA224+CD8+ and data not shown for DbPB1703+CD8+ and KbPB1-F262+CD8+). Data represent the mean proportion of a particular peptide-specific CD8+ population. * = p<0.01 shows a difference between young and aged animals. Experimental outline as in Figure 1AB.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285595&req=5

ppat-1002544-g002: Immunodominance hierarchies in aged mice after 10 infection or 20 challenge of primed-early mice.The relative prevalence of the immunodominant DbNP366+CD8+ and DbPA224+CD8+ T cell population over the subdominant DbPB1703+CD8+ and KbPB1-F262+CD8+ sets. Results are shown for (A, B) 10 and (C, D) 20 HK infection in (A, C) young and (B, D) aged mice. The relative contributions of particular antigen-specific CD8+ T cells were analysed based on total cell responses (Figure 1 for DbNP366+CD8+ and DbPA224+CD8+ and data not shown for DbPB1703+CD8+ and KbPB1-F262+CD8+). Data represent the mean proportion of a particular peptide-specific CD8+ population. * = p<0.01 shows a difference between young and aged animals. Experimental outline as in Figure 1AB.
Mentions: The beneficial effect of the early CD8+ priming on the immunodominant low-precursor responses like the DbNP366-specific population following influenza infection at the extreme age was most striking when the relative contributions of particular antigen-specific CD8+ T cells were analysed based on total cell numbers (Figure 2, calculations based on Figure 1 for immunodominant DbNP366+CD8+ and DbPA224+CD8+ pools, and data not shown for subdominant DbPB1703+CD8+ and KbPB1-F262+CD8+ populations). In the aged mice, the primary CD8+ T cell responses showed a shift in the typical immunodominance hierarchy (Figure 2B), with the contribution of the immunodominant DbNP366+CD8+ population being significantly lower in the aged mice (9.4±3.6%) in comparison to young animals (43.4±15%; p<0.01; Figure 2A). The differential immunodominance hierarchy resulted mainly from significantly increased contribution of KbPB1703+CD8+ T cells (Figure 2). This led to major modifications in response hierarchy following primary influenza virus infection of aged mice KbPB1703>DbPA224>DbPB1-F262>DbNP366, with the comparable profile for young mice being DbNP366>DbPA224 = KbPB1703≫DbPB1-F262.

Bottom Line: However, late priming resulted in reduced TCRβ diversity in comparison with vaccination earlier in life.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Melbourne, Parkville, Melbourne, Australia.

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.

Show MeSH
Related in: MedlinePlus