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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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Related in: MedlinePlus

Priming at an extreme age leads to normal secondary influenza-specific CD8+ T cell responses.(A) For the secondary responses of the old-primed mice, naïve B6 mice were i.p. primed with 1.5×107 pfu of the PR8 virus either at 6 weeks of age (young mice) or at 22 months (primed late aged mice), followed by a secondary i.n. challenge with 1×104 pfu of the HK influenza strain 6 weeks later. (B) The magnitude of CD8+ T cell responses in the spleen at the peak (d8) of secondary phase following influenza virus infection are shown for young (6–8 weeks) and aged (22 months old) B6 mice. Immunodominant DbNP366+ and DbPA224+ influenza-specific CD8+ T cell responses were assessed by IFN-γ production in an ex vivo ICS assay. (C, D) Polyfunctionality of influenza-specific CD8+ T cell responses was assessed by simultaneous production of IFN-γ, TNF-α and IL-2 in the spleen and of young and aged mice. (E) The contribution of immunodominant DbNP366+CD8+ and DbPA224+CD8+ T cell responses in comparison to subdominant DbPB1703+CD8+ and KbPB1-F262+CD8+ sets was calculated based on the proportions of IFN-γ+CD8+ populations depicted in (B for DbNP366+CD8+ and DbPA224+CD8+ and data not shown for DbPB1703+CD8+ and KbPB1-F262+CD8+). TCR Vβ usage for the (F) DbNP366 and (G) DbPA224 CD8+ sets in the spleen of recall responses of mice primed late. TCR Vβ results represent individual mice of 3 per group. * = p<0.05.
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ppat-1002544-g006: Priming at an extreme age leads to normal secondary influenza-specific CD8+ T cell responses.(A) For the secondary responses of the old-primed mice, naïve B6 mice were i.p. primed with 1.5×107 pfu of the PR8 virus either at 6 weeks of age (young mice) or at 22 months (primed late aged mice), followed by a secondary i.n. challenge with 1×104 pfu of the HK influenza strain 6 weeks later. (B) The magnitude of CD8+ T cell responses in the spleen at the peak (d8) of secondary phase following influenza virus infection are shown for young (6–8 weeks) and aged (22 months old) B6 mice. Immunodominant DbNP366+ and DbPA224+ influenza-specific CD8+ T cell responses were assessed by IFN-γ production in an ex vivo ICS assay. (C, D) Polyfunctionality of influenza-specific CD8+ T cell responses was assessed by simultaneous production of IFN-γ, TNF-α and IL-2 in the spleen and of young and aged mice. (E) The contribution of immunodominant DbNP366+CD8+ and DbPA224+CD8+ T cell responses in comparison to subdominant DbPB1703+CD8+ and KbPB1-F262+CD8+ sets was calculated based on the proportions of IFN-γ+CD8+ populations depicted in (B for DbNP366+CD8+ and DbPA224+CD8+ and data not shown for DbPB1703+CD8+ and KbPB1-F262+CD8+). TCR Vβ usage for the (F) DbNP366 and (G) DbPA224 CD8+ sets in the spleen of recall responses of mice primed late. TCR Vβ results represent individual mice of 3 per group. * = p<0.05.

Mentions: Since priming at a young age led to the typical magnitude and quality of influenza-specific CD8+ T cell responses following viral infection in the aged mice, we asked whether priming the mice via a non-replicative route (i.p. priming with 1.5×107 pfu of PR8) at extreme age (22 months) would be also beneficial for the subsequent influenza virus infection. Since the reduced primary DbNP366+CD8+ T cell responses in aged mice has been attributed to the lower naïve precursors in young mice [5], this experiment would determine whether old naive mice could be primed at an extreme age (at 22 months) and subsequently challenged i.n. with 1×104 pfu of the HK influenza strain (at ∼24 months; Figure 6A) to mount an effective recall response after the attrition had occurred. Surprisingly, despite the reduced primary DbNP366+CD8+ T cell responses (Figure 1C) and lower magnitude of secondary DbPA224+CD8+ sets (Figure 1E) in the spleens of aged animals, the recall of influenza-specific CD8+ T cells was robust and equivalent in magnitude to the young controls (Figure 6). The numbers of both immunodominant DbNP366+CD8+ and DbPA224+CD8+ populations were normal (Figure 6B). This resulted in the maintained contribution of each of the T cell specificities to influenza-specific responses (Figure 6E). Conversely, the polyfunctionality of those secondary CD8+ T cell populations in mice primed at the extreme age did not always resemble effectiveness of influenza-specific CD8+ T cells recruited in young individuals (Figure 6C). Perturbations in the TCR usage with extreme age were evident macroscopically in the TCR Vβ usage for DbPA224+CD8+ (Figure 6G) and especially the DbNP366+CD8+ (Figure 6F) responses, with the usage of alternate Vβ8.1/8.2 for DbPA224+CD8+, and Vβ7 and Vβ8.1/8.2 for DbNP366+CD8+ populations. The characteristic Vβ8.3 usage for DbNP366+CD8+ was only dominant in 1 of 4 mice (Figure 6F), reflecting narrowing of the naïve DbNP366+CD8+ set with extreme age that initially limited the primary response (Figure 1C) and/or the clonal expansions characteristic for the aged animals as previously reported [13], [14].


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)

Priming at an extreme age leads to normal secondary influenza-specific CD8+ T cell responses.(A) For the secondary responses of the old-primed mice, naïve B6 mice were i.p. primed with 1.5×107 pfu of the PR8 virus either at 6 weeks of age (young mice) or at 22 months (primed late aged mice), followed by a secondary i.n. challenge with 1×104 pfu of the HK influenza strain 6 weeks later. (B) The magnitude of CD8+ T cell responses in the spleen at the peak (d8) of secondary phase following influenza virus infection are shown for young (6–8 weeks) and aged (22 months old) B6 mice. Immunodominant DbNP366+ and DbPA224+ influenza-specific CD8+ T cell responses were assessed by IFN-γ production in an ex vivo ICS assay. (C, D) Polyfunctionality of influenza-specific CD8+ T cell responses was assessed by simultaneous production of IFN-γ, TNF-α and IL-2 in the spleen and of young and aged mice. (E) The contribution of immunodominant DbNP366+CD8+ and DbPA224+CD8+ T cell responses in comparison to subdominant DbPB1703+CD8+ and KbPB1-F262+CD8+ sets was calculated based on the proportions of IFN-γ+CD8+ populations depicted in (B for DbNP366+CD8+ and DbPA224+CD8+ and data not shown for DbPB1703+CD8+ and KbPB1-F262+CD8+). TCR Vβ usage for the (F) DbNP366 and (G) DbPA224 CD8+ sets in the spleen of recall responses of mice primed late. TCR Vβ results represent individual mice of 3 per group. * = p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1002544-g006: Priming at an extreme age leads to normal secondary influenza-specific CD8+ T cell responses.(A) For the secondary responses of the old-primed mice, naïve B6 mice were i.p. primed with 1.5×107 pfu of the PR8 virus either at 6 weeks of age (young mice) or at 22 months (primed late aged mice), followed by a secondary i.n. challenge with 1×104 pfu of the HK influenza strain 6 weeks later. (B) The magnitude of CD8+ T cell responses in the spleen at the peak (d8) of secondary phase following influenza virus infection are shown for young (6–8 weeks) and aged (22 months old) B6 mice. Immunodominant DbNP366+ and DbPA224+ influenza-specific CD8+ T cell responses were assessed by IFN-γ production in an ex vivo ICS assay. (C, D) Polyfunctionality of influenza-specific CD8+ T cell responses was assessed by simultaneous production of IFN-γ, TNF-α and IL-2 in the spleen and of young and aged mice. (E) The contribution of immunodominant DbNP366+CD8+ and DbPA224+CD8+ T cell responses in comparison to subdominant DbPB1703+CD8+ and KbPB1-F262+CD8+ sets was calculated based on the proportions of IFN-γ+CD8+ populations depicted in (B for DbNP366+CD8+ and DbPA224+CD8+ and data not shown for DbPB1703+CD8+ and KbPB1-F262+CD8+). TCR Vβ usage for the (F) DbNP366 and (G) DbPA224 CD8+ sets in the spleen of recall responses of mice primed late. TCR Vβ results represent individual mice of 3 per group. * = p<0.05.
Mentions: Since priming at a young age led to the typical magnitude and quality of influenza-specific CD8+ T cell responses following viral infection in the aged mice, we asked whether priming the mice via a non-replicative route (i.p. priming with 1.5×107 pfu of PR8) at extreme age (22 months) would be also beneficial for the subsequent influenza virus infection. Since the reduced primary DbNP366+CD8+ T cell responses in aged mice has been attributed to the lower naïve precursors in young mice [5], this experiment would determine whether old naive mice could be primed at an extreme age (at 22 months) and subsequently challenged i.n. with 1×104 pfu of the HK influenza strain (at ∼24 months; Figure 6A) to mount an effective recall response after the attrition had occurred. Surprisingly, despite the reduced primary DbNP366+CD8+ T cell responses (Figure 1C) and lower magnitude of secondary DbPA224+CD8+ sets (Figure 1E) in the spleens of aged animals, the recall of influenza-specific CD8+ T cells was robust and equivalent in magnitude to the young controls (Figure 6). The numbers of both immunodominant DbNP366+CD8+ and DbPA224+CD8+ populations were normal (Figure 6B). This resulted in the maintained contribution of each of the T cell specificities to influenza-specific responses (Figure 6E). Conversely, the polyfunctionality of those secondary CD8+ T cell populations in mice primed at the extreme age did not always resemble effectiveness of influenza-specific CD8+ T cells recruited in young individuals (Figure 6C). Perturbations in the TCR usage with extreme age were evident macroscopically in the TCR Vβ usage for DbPA224+CD8+ (Figure 6G) and especially the DbNP366+CD8+ (Figure 6F) responses, with the usage of alternate Vβ8.1/8.2 for DbPA224+CD8+, and Vβ7 and Vβ8.1/8.2 for DbNP366+CD8+ populations. The characteristic Vβ8.3 usage for DbNP366+CD8+ was only dominant in 1 of 4 mice (Figure 6F), reflecting narrowing of the naïve DbNP366+CD8+ set with extreme age that initially limited the primary response (Figure 1C) and/or the clonal expansions characteristic for the aged animals as previously reported [13], [14].

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