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

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.DOI: http://dx.doi.org/10.7554/eLife.03706.001

Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1

“…54 Two recently published findings indicate that autophagy is critical in the regulation of memory CD8 + T cells using virus infection models. 10,11 Autophagy is reduced in T cells from aging mice and enhancing autophagy could restore CD8 memory response. 11 Our data provides new clues and explanations for these published findings.…”

“…5,6 Autophagy plays an essential role in the development and function of T lymphocytes. Autophagy regulates the calcium mobilization and energy metabolism in T cells, [7][8][9] is critical for effector CD8 + T cell survival and memory formation, 10,11 promotes the proliferation and survival of invariant NKT cells 12,13 and tunes down TCR signaling by degrading BCL10. 14 Autophagy starts with a membrane precursor called the phagophore.…”

Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans?

“…Intriguingly, external supplementation of spermidine exerts various beneficial effects on aging and age-related disease in a variety of model organisms, including mice [5,6]. For example, spermidine feeding extends lifespan across species [5,7,8], promotes cardio- [5] and neuroprotection [9–11], stimulates antineoplastic immune response [12] and may avoid immunosenescence by stimulating memory T-cell formation [13,14]. Many of these anti-aging properties have been causally linked to the capacity of spermidine to ensure proteostasis through the stimulation of cytoprotective macroautophagy [15–17].…”

L’autophagie et l’homéostasie des lymphocytes T et B

“…Les souspopulations de lymphocytes Th1 et Th2 montrent une moins bonne survie que les Th17 après stimulation en absence d'autophagie. L'autophagie joue un rôle important dans l'évolution du métabolisme des LT CD8 + effectrices lors de leur transition en cellules mémoire [36,37]. L'autophagie, dans ce cas, paraît nécessaire au maintien du métabolisme lié à l'oxydation des acides gras, probablement de par le contrôle du bon fonctionnement de l'activité mitochondriale.…”

“…Les équipes de Simon et d'Ahmed ont en effet montré que l'autophagie était indispensable au maintien des cellules T CD8 + mémoire (Figure 3) [36,37]. Afin de résoudre les problèmes rencontrés dans les modèles que nous avons décrits plus haut pour la survie basale des LT déficients en autophagie, Ahmed et al ont utilisé un modèle permettant l'inactivation de l'autophagie au seul stade effecteur des cellules T CD8 + .…”