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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

Atg7−/− CD8+ T cells fail to mount robust re-call responses to secondary infection.(A) Recall CD8+ T cell responses in WT and T-Atg7−/− mice. Mice were immunized once with PR8 influenza (n = 4); twice with PR8+X31 influenza (n = 6); or three times with PR8 + X31 + PR8 (n = 4). Absolute counts of CD8+ NP-tetramer+ T cells were determined in the lungs at either day 24 (PR8), or day 5 post–challenge (PR8 + X31 & PR8 + X31 + PR8). All values are mean ± s.e.m.DOI:http://dx.doi.org/10.7554/eLife.03706.013
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fig5s1: Atg7−/− CD8+ T cells fail to mount robust re-call responses to secondary infection.(A) Recall CD8+ T cell responses in WT and T-Atg7−/− mice. Mice were immunized once with PR8 influenza (n = 4); twice with PR8+X31 influenza (n = 6); or three times with PR8 + X31 + PR8 (n = 4). Absolute counts of CD8+ NP-tetramer+ T cells were determined in the lungs at either day 24 (PR8), or day 5 post–challenge (PR8 + X31 & PR8 + X31 + PR8). All values are mean ± s.e.m.DOI:http://dx.doi.org/10.7554/eLife.03706.013

Mentions: We then tested whether T-Atg7−/− mice were able to mount a recall CD8+ T cell response to a secondary infection. We primed T-Atg7−/− mice with PR8 (H1N1) followed by heterologous challenge with the X31 strain of influenza (H3N2). By challenging with a heterologous virus strain expressing different surface antigens, it is possible to significantly diminish the influence of antibodies in mediating immunity to secondary infection. Thus, heterotypic immunity relies heavily on cross-reactive CD8+ T cell responses (Zweerink et al., 1977; Townsend et al., 1986), as opposed to homotypic immunity (for example PR8 primed, PR8 challenged) to which influenza-specific antibodies contribute (Townsend et al., 1986; Epstein and Price, 2010). While the wild-type mice mounted a fast and strong recall response upon X31 challenge in PR8-primed mice (PR8 + X31), this was drastically diminished in T-Atg7−/− mice in the lungs on day 5 (Figure 5A, absolute counts in Figure 5—figure supplement 1A). Even when three live virus immunizations were administered (PR8 primed, challenged with X31 then with PR8), T-Atg7−/− mice were unable to mount recall responses. Surprisingly, T-Atg7−/− mice survived the heterotypic viral challenges despite the vastly diminished numbers of secondary CD8+ Teff.10.7554/eLife.03706.012Figure 5.Atg7−/− memory CD8+ T cells mount a significantly reduced recall response to secondary immunization.


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)

Atg7−/− CD8+ T cells fail to mount robust re-call responses to secondary infection.(A) Recall CD8+ T cell responses in WT and T-Atg7−/− mice. Mice were immunized once with PR8 influenza (n = 4); twice with PR8+X31 influenza (n = 6); or three times with PR8 + X31 + PR8 (n = 4). Absolute counts of CD8+ NP-tetramer+ T cells were determined in the lungs at either day 24 (PR8), or day 5 post–challenge (PR8 + X31 & PR8 + X31 + PR8). All values are mean ± s.e.m.DOI:http://dx.doi.org/10.7554/eLife.03706.013
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5s1: Atg7−/− CD8+ T cells fail to mount robust re-call responses to secondary infection.(A) Recall CD8+ T cell responses in WT and T-Atg7−/− mice. Mice were immunized once with PR8 influenza (n = 4); twice with PR8+X31 influenza (n = 6); or three times with PR8 + X31 + PR8 (n = 4). Absolute counts of CD8+ NP-tetramer+ T cells were determined in the lungs at either day 24 (PR8), or day 5 post–challenge (PR8 + X31 & PR8 + X31 + PR8). All values are mean ± s.e.m.DOI:http://dx.doi.org/10.7554/eLife.03706.013
Mentions: We then tested whether T-Atg7−/− mice were able to mount a recall CD8+ T cell response to a secondary infection. We primed T-Atg7−/− mice with PR8 (H1N1) followed by heterologous challenge with the X31 strain of influenza (H3N2). By challenging with a heterologous virus strain expressing different surface antigens, it is possible to significantly diminish the influence of antibodies in mediating immunity to secondary infection. Thus, heterotypic immunity relies heavily on cross-reactive CD8+ T cell responses (Zweerink et al., 1977; Townsend et al., 1986), as opposed to homotypic immunity (for example PR8 primed, PR8 challenged) to which influenza-specific antibodies contribute (Townsend et al., 1986; Epstein and Price, 2010). While the wild-type mice mounted a fast and strong recall response upon X31 challenge in PR8-primed mice (PR8 + X31), this was drastically diminished in T-Atg7−/− mice in the lungs on day 5 (Figure 5A, absolute counts in Figure 5—figure supplement 1A). Even when three live virus immunizations were administered (PR8 primed, challenged with X31 then with PR8), T-Atg7−/− mice were unable to mount recall responses. Surprisingly, T-Atg7−/− mice survived the heterotypic viral challenges despite the vastly diminished numbers of secondary CD8+ Teff.10.7554/eLife.03706.012Figure 5.Atg7−/− memory CD8+ T cells mount a significantly reduced recall response to secondary immunization.

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