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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: 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.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

T-Atg7−/− mice fail to form memory CD8+ T cells to a conventional MCMV epitope.(A) Effector CD8+ T cell absolute counts in WT and T-Atg7−/− mice. Quantification of the absolute number of CD8+ NP-tetramer+ T cells was determined in the lungs on day 10 of PR8 influenza infection. **p = 0.0084 by Student t test (n = 6–9). (B) Frequency of m45-specific CD8+ T cells in the liver of MCMV-immunized WT and T-Atg7−/− mice on day 100 post-infection. Dot plots are gated on CD8+ T cells; bar graphs depict the percentage of CD8+ T cells that are m45-tetramer+. All values are mean ± s.e.m.DOI:http://dx.doi.org/10.7554/eLife.03706.007
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fig2s1: T-Atg7−/− mice fail to form memory CD8+ T cells to a conventional MCMV epitope.(A) Effector CD8+ T cell absolute counts in WT and T-Atg7−/− mice. Quantification of the absolute number of CD8+ NP-tetramer+ T cells was determined in the lungs on day 10 of PR8 influenza infection. **p = 0.0084 by Student t test (n = 6–9). (B) Frequency of m45-specific CD8+ T cells in the liver of MCMV-immunized WT and T-Atg7−/− mice on day 100 post-infection. Dot plots are gated on CD8+ T cells; bar graphs depict the percentage of CD8+ T cells that are m45-tetramer+. All values are mean ± s.e.m.DOI:http://dx.doi.org/10.7554/eLife.03706.007

Mentions: Previous studies have shown a role for autophagy in naive T cell organelle homeostasis and survival (Pua et al., 2009; Jia and He, 2011). However, the importance of autophagy in CD8+ T cells responding to infection is unknown. To investigate this, we challenged T-Atg7−/− mice with influenza (PR8 strain) and MCMV. In T-Atg7−/− mice, we found normal expansion of the antigen-specific effector CD8+ T cell (CD8+ Teff) compartment using influenza-specific tetramers on day 10 (peak response) in the lungs (Figure 2A). However, due to the pre-existing lymphopenia observed in naïve mice, the absolute counts were diminished (Figure 2—figure supplement 1A). The CD8+ Teff response to MCMV in the blood on day 7 was also normal (Figure 2B) (Hutchinson et al., 2011). However, the ability of T-Atg7−/− mice to form memory CD8+ T cells (CD8+ Tmem) to both influenza and MCMV is severely compromised (Figure 2C,D). Performing serial bleeding on influenza infected mice over time, we demonstrated a catastrophic collapse of the antigen-specific CD8+ T cell pool at day 21, resulting in a failure to retain CD8+ Tmem in T-Atg7−/− mice (Figure 2E). Interestingly, the response to the ‘inflationary’ epitopes m38 and IE3 from MCMV is also compromised (Figure 2F). In response to these epitopes, wild-type CD8+ T cells continue to expand throughout MCMV chronic infection. However, Atg7−/− CD8+ T cells fail to inflate and instead undergo a dramatic contraction leading to a failure to form a MCMV-specific CD8+ T cell memory pool. This profound CD8+ T cell contraction in T-Atg7−/− mice is also observed in response to a conventional, non-inflating MCMV epitope (m45, Figure 2—figure supplement 1B). While viral titers against influenza in the lungs of wild-type and T-Atg7−/− mice were comparable at day 3 of infection, they were significantly higher on day 6 in T-Atg7−/− mice (Figure 2G). This is most likely due to the significantly lower absolute number of antigen-specific effector CD8+ T cells. As T-Atg7−/− mice survived influenza challenge, we expect that the virus is eventually cleared in all mice. In keeping with these findings, autophagy levels (CytoID) are significantly increased in the antigen-specific CD8+ T cell compartment compared to naïve T cells (CD44lo) in response to influenza in both spleen (Figure 2H) and lungs (Figure 2I), indicating autophagy is induced upon antigen stimulation in vivo.10.7554/eLife.03706.006Figure 2.Normal effector CD8+ T cell responses to viral infection but defective memory CD8+ T cell formation in T-Atg7−/− 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)

T-Atg7−/− mice fail to form memory CD8+ T cells to a conventional MCMV epitope.(A) Effector CD8+ T cell absolute counts in WT and T-Atg7−/− mice. Quantification of the absolute number of CD8+ NP-tetramer+ T cells was determined in the lungs on day 10 of PR8 influenza infection. **p = 0.0084 by Student t test (n = 6–9). (B) Frequency of m45-specific CD8+ T cells in the liver of MCMV-immunized WT and T-Atg7−/− mice on day 100 post-infection. Dot plots are gated on CD8+ T cells; bar graphs depict the percentage of CD8+ T cells that are m45-tetramer+. All values are mean ± s.e.m.DOI:http://dx.doi.org/10.7554/eLife.03706.007
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4225493&req=5

fig2s1: T-Atg7−/− mice fail to form memory CD8+ T cells to a conventional MCMV epitope.(A) Effector CD8+ T cell absolute counts in WT and T-Atg7−/− mice. Quantification of the absolute number of CD8+ NP-tetramer+ T cells was determined in the lungs on day 10 of PR8 influenza infection. **p = 0.0084 by Student t test (n = 6–9). (B) Frequency of m45-specific CD8+ T cells in the liver of MCMV-immunized WT and T-Atg7−/− mice on day 100 post-infection. Dot plots are gated on CD8+ T cells; bar graphs depict the percentage of CD8+ T cells that are m45-tetramer+. All values are mean ± s.e.m.DOI:http://dx.doi.org/10.7554/eLife.03706.007
Mentions: Previous studies have shown a role for autophagy in naive T cell organelle homeostasis and survival (Pua et al., 2009; Jia and He, 2011). However, the importance of autophagy in CD8+ T cells responding to infection is unknown. To investigate this, we challenged T-Atg7−/− mice with influenza (PR8 strain) and MCMV. In T-Atg7−/− mice, we found normal expansion of the antigen-specific effector CD8+ T cell (CD8+ Teff) compartment using influenza-specific tetramers on day 10 (peak response) in the lungs (Figure 2A). However, due to the pre-existing lymphopenia observed in naïve mice, the absolute counts were diminished (Figure 2—figure supplement 1A). The CD8+ Teff response to MCMV in the blood on day 7 was also normal (Figure 2B) (Hutchinson et al., 2011). However, the ability of T-Atg7−/− mice to form memory CD8+ T cells (CD8+ Tmem) to both influenza and MCMV is severely compromised (Figure 2C,D). Performing serial bleeding on influenza infected mice over time, we demonstrated a catastrophic collapse of the antigen-specific CD8+ T cell pool at day 21, resulting in a failure to retain CD8+ Tmem in T-Atg7−/− mice (Figure 2E). Interestingly, the response to the ‘inflationary’ epitopes m38 and IE3 from MCMV is also compromised (Figure 2F). In response to these epitopes, wild-type CD8+ T cells continue to expand throughout MCMV chronic infection. However, Atg7−/− CD8+ T cells fail to inflate and instead undergo a dramatic contraction leading to a failure to form a MCMV-specific CD8+ T cell memory pool. This profound CD8+ T cell contraction in T-Atg7−/− mice is also observed in response to a conventional, non-inflating MCMV epitope (m45, Figure 2—figure supplement 1B). While viral titers against influenza in the lungs of wild-type and T-Atg7−/− mice were comparable at day 3 of infection, they were significantly higher on day 6 in T-Atg7−/− mice (Figure 2G). This is most likely due to the significantly lower absolute number of antigen-specific effector CD8+ T cells. As T-Atg7−/− mice survived influenza challenge, we expect that the virus is eventually cleared in all mice. In keeping with these findings, autophagy levels (CytoID) are significantly increased in the antigen-specific CD8+ T cell compartment compared to naïve T cells (CD44lo) in response to influenza in both spleen (Figure 2H) and lungs (Figure 2I), indicating autophagy is induced upon antigen stimulation in vivo.10.7554/eLife.03706.006Figure 2.Normal effector CD8+ T cell responses to viral infection but defective memory CD8+ T cell formation in T-Atg7−/− mice.

Bottom Line: 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.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