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Autophagy is a critical regulator of memory CD8(+) T cell formation.

Puleston DJ, Zhang H, Powell TJ, Lipina E, Sims S, Panse I, Watson AS, Cerundolo V, Townsend AR, Klenerman P, Simon AK - Elife (2014)

Bottom Line: Interestingly, autophagy levels were diminished in CD8(+) T cells from aged mice.We could rejuvenate CD8(+) T cell responses in elderly mice in an autophagy dependent manner using the compound spermidine.This study reveals a cell intrinsic explanation for poor CD8(+) T cell memory in the elderly and potentially offers novel immune modulators to improve aged immunity.

View Article: PubMed Central - PubMed

Affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

ABSTRACT
During infection, CD8(+) T cells initially expand then contract, leaving a small memory pool providing long lasting immunity. While it has been described that CD8(+) T cell memory formation becomes defective in old age, the cellular mechanism is largely unknown. Autophagy is a major cellular lysosomal degradation pathway of bulk material, and levels are known to fall with age. In this study, we describe a novel role for autophagy in CD8(+) T cell memory formation. Mice lacking the autophagy gene Atg7 in T cells failed to establish CD8(+) T cell memory to influenza and MCMV infection. Interestingly, autophagy levels were diminished in CD8(+) T cells from aged mice. We could rejuvenate CD8(+) T cell responses in elderly mice in an autophagy dependent manner using the compound spermidine. This study reveals a cell intrinsic explanation for poor CD8(+) T cell memory in the elderly and potentially offers novel immune modulators to improve aged immunity.

No MeSH data available.


Related in: MedlinePlus

Autophagy levels are significantly diminished in antigen-specific CD8+ T cells from aged mice.Autophagy levels by CytoID (A) and LC3-II staining (B) in antigen-specific CD8+ T cells from young and old mice. 8-week-old and 2 year old mice were immunized with PR8 influenza. On day 10 post-infection lungs were harvested and stained with CytoID or for LC3-II to assess autophagy levels in NP-Tetramer+ CD8+ T cells by flow cytometry. (A) ****p < 0.0001 (n = 7). (B) **p = 0.0056, (n = 7).DOI:http://dx.doi.org/10.7554/eLife.03706.015
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fig6s1: Autophagy levels are significantly diminished in antigen-specific CD8+ T cells from aged mice.Autophagy levels by CytoID (A) and LC3-II staining (B) in antigen-specific CD8+ T cells from young and old mice. 8-week-old and 2 year old mice were immunized with PR8 influenza. On day 10 post-infection lungs were harvested and stained with CytoID or for LC3-II to assess autophagy levels in NP-Tetramer+ CD8+ T cells by flow cytometry. (A) ****p < 0.0001 (n = 7). (B) **p = 0.0056, (n = 7).DOI:http://dx.doi.org/10.7554/eLife.03706.015

Mentions: We addressed whether diminished CD8+ Tmem formation can be improved in the elderly by modulating autophagy. First, we showed that mRNA levels of essential autophagy genes are decreased in sorted CD8+ T cells from naïve old mice (2 years) as compared to young mice (8 weeks). The CD8+ CD44hi memory compartment is particularly affected (Figure 6A). CD8+ T cells from old mice also showed significantly decreased autophagic flux detected by counting LC3 spots in NP-specific CD8+ T cells from young and old mice both in the presence and absence of an autophagy flux inhibitor (Figure 6B,C). This was confirmed by using two flow cytometry based autophagy detection, also in NP-specific CD8+ T cells (Figure 6—figure supplement 1A and B).10.7554/eLife.03706.014Figure 6.Boosting autophagy restores CD8+ T cell responses to vaccination in elderly mice.


Autophagy is a critical regulator of memory CD8(+) T cell formation.

Puleston DJ, Zhang H, Powell TJ, Lipina E, Sims S, Panse I, Watson AS, Cerundolo V, Townsend AR, Klenerman P, Simon AK - Elife (2014)

Autophagy levels are significantly diminished in antigen-specific CD8+ T cells from aged mice.Autophagy levels by CytoID (A) and LC3-II staining (B) in antigen-specific CD8+ T cells from young and old mice. 8-week-old and 2 year old mice were immunized with PR8 influenza. On day 10 post-infection lungs were harvested and stained with CytoID or for LC3-II to assess autophagy levels in NP-Tetramer+ CD8+ T cells by flow cytometry. (A) ****p < 0.0001 (n = 7). (B) **p = 0.0056, (n = 7).DOI:http://dx.doi.org/10.7554/eLife.03706.015
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4225493&req=5

fig6s1: Autophagy levels are significantly diminished in antigen-specific CD8+ T cells from aged mice.Autophagy levels by CytoID (A) and LC3-II staining (B) in antigen-specific CD8+ T cells from young and old mice. 8-week-old and 2 year old mice were immunized with PR8 influenza. On day 10 post-infection lungs were harvested and stained with CytoID or for LC3-II to assess autophagy levels in NP-Tetramer+ CD8+ T cells by flow cytometry. (A) ****p < 0.0001 (n = 7). (B) **p = 0.0056, (n = 7).DOI:http://dx.doi.org/10.7554/eLife.03706.015
Mentions: We addressed whether diminished CD8+ Tmem formation can be improved in the elderly by modulating autophagy. First, we showed that mRNA levels of essential autophagy genes are decreased in sorted CD8+ T cells from naïve old mice (2 years) as compared to young mice (8 weeks). The CD8+ CD44hi memory compartment is particularly affected (Figure 6A). CD8+ T cells from old mice also showed significantly decreased autophagic flux detected by counting LC3 spots in NP-specific CD8+ T cells from young and old mice both in the presence and absence of an autophagy flux inhibitor (Figure 6B,C). This was confirmed by using two flow cytometry based autophagy detection, also in NP-specific CD8+ T cells (Figure 6—figure supplement 1A and B).10.7554/eLife.03706.014Figure 6.Boosting autophagy restores CD8+ T cell responses to vaccination in elderly mice.

Bottom Line: Interestingly, autophagy levels were diminished in CD8(+) T cells from aged mice.We could rejuvenate CD8(+) T cell responses in elderly mice in an autophagy dependent manner using the compound spermidine.This study reveals a cell intrinsic explanation for poor CD8(+) T cell memory in the elderly and potentially offers novel immune modulators to improve aged immunity.

View Article: PubMed Central - PubMed

Affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

ABSTRACT
During infection, CD8(+) T cells initially expand then contract, leaving a small memory pool providing long lasting immunity. While it has been described that CD8(+) T cell memory formation becomes defective in old age, the cellular mechanism is largely unknown. Autophagy is a major cellular lysosomal degradation pathway of bulk material, and levels are known to fall with age. In this study, we describe a novel role for autophagy in CD8(+) T cell memory formation. Mice lacking the autophagy gene Atg7 in T cells failed to establish CD8(+) T cell memory to influenza and MCMV infection. Interestingly, autophagy levels were diminished in CD8(+) T cells from aged mice. We could rejuvenate CD8(+) T cell responses in elderly mice in an autophagy dependent manner using the compound spermidine. This study reveals a cell intrinsic explanation for poor CD8(+) T cell memory in the elderly and potentially offers novel immune modulators to improve aged immunity.

No MeSH data available.


Related in: MedlinePlus