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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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Impaired polyfunctionality of DbPA224-specific CD8+ T cells in the aged mice during primary but not secondary influenza infection.(A) Primary or (B) secondary (primed young) influenza-specific CD8+ T cell responses were assessed for simultaneous production of IFN-γ, TNF-α and IL-2 in the spleen of aged (22 months old) and young (6–8 weeks) mice. Compiled data (n = 3–5, mean±SD) are shown for the mean fluorescence intensity (MFI) of IFN-γ, IFN-γ and TNF-α as well as IFN-γ and IL-2 staining. * = p<0.05. Experimental outline as in Figure 1AB.
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ppat-1002544-g004: Impaired polyfunctionality of DbPA224-specific CD8+ T cells in the aged mice during primary but not secondary influenza infection.(A) Primary or (B) secondary (primed young) influenza-specific CD8+ T cell responses were assessed for simultaneous production of IFN-γ, TNF-α and IL-2 in the spleen of aged (22 months old) and young (6–8 weeks) mice. Compiled data (n = 3–5, mean±SD) are shown for the mean fluorescence intensity (MFI) of IFN-γ, IFN-γ and TNF-α as well as IFN-γ and IL-2 staining. * = p<0.05. Experimental outline as in Figure 1AB.

Mentions: One measure of CD8+ T cell function is the capacity to produce multiple cytokines simultaneously [39] following in vitro stimulation with peptide in the standard, 5 h ICS assay. For the primary DbPA224+CD8+ T cell population that remained relatively constant in numbers with age (Figure 1C), the frequencies of double (IFN-γ/TNF-α) and triple-producers (IFN-γ/TNF-α/IL-2) were significantly lower in comparison with the young mice (Figure 3AB). Furthermore, taking mean fluorescence intensity (MFI), which represents the intensity and therefore amount of cytokine production, it also seems that the DbPA224+CD8+ population tended to produce less TNF-α, though this diminution effect was not apparent for either IFN-γ or IL-2 (Figure 4A). Taking the prevalence and MFI data together (Figure 3 and Figure 4), there appears to be a general decrease in cytokine polyfunctionality for the primary DbPA224+CD8+ response.


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)

Impaired polyfunctionality of DbPA224-specific CD8+ T cells in the aged mice during primary but not secondary influenza infection.(A) Primary or (B) secondary (primed young) influenza-specific CD8+ T cell responses were assessed for simultaneous production of IFN-γ, TNF-α and IL-2 in the spleen of aged (22 months old) and young (6–8 weeks) mice. Compiled data (n = 3–5, mean±SD) are shown for the mean fluorescence intensity (MFI) of IFN-γ, IFN-γ and TNF-α as well as IFN-γ and IL-2 staining. * = p<0.05. Experimental outline as in Figure 1AB.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1002544-g004: Impaired polyfunctionality of DbPA224-specific CD8+ T cells in the aged mice during primary but not secondary influenza infection.(A) Primary or (B) secondary (primed young) influenza-specific CD8+ T cell responses were assessed for simultaneous production of IFN-γ, TNF-α and IL-2 in the spleen of aged (22 months old) and young (6–8 weeks) mice. Compiled data (n = 3–5, mean±SD) are shown for the mean fluorescence intensity (MFI) of IFN-γ, IFN-γ and TNF-α as well as IFN-γ and IL-2 staining. * = p<0.05. Experimental outline as in Figure 1AB.
Mentions: One measure of CD8+ T cell function is the capacity to produce multiple cytokines simultaneously [39] following in vitro stimulation with peptide in the standard, 5 h ICS assay. For the primary DbPA224+CD8+ T cell population that remained relatively constant in numbers with age (Figure 1C), the frequencies of double (IFN-γ/TNF-α) and triple-producers (IFN-γ/TNF-α/IL-2) were significantly lower in comparison with the young mice (Figure 3AB). Furthermore, taking mean fluorescence intensity (MFI), which represents the intensity and therefore amount of cytokine production, it also seems that the DbPA224+CD8+ population tended to produce less TNF-α, though this diminution effect was not apparent for either IFN-γ or IL-2 (Figure 4A). Taking the prevalence and MFI data together (Figure 3 and Figure 4), there appears to be a general decrease in cytokine polyfunctionality for the primary DbPA224+CD8+ response.

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