Aging of Antiviral CD8+ Memory T Cells Fosters Increased Survival, Metabolic Adaptations, and Lymphoid Tissue Homing

Abstract

Aging of established antiviral T cell memory can foster a series of progressive adaptations that paradoxically improve rather than compromise protective CD8+ T cell immunity. We now provide evidence that this gradual evolution, the pace of which is contingent on the precise context of the primary response, also impinges on the molecular mechanisms that regulate CD8+ memory T cell (TM) homeostasis. Over time, CD8+ TM generated in the wake of an acute infection with the natural murine pathogen lymphocytic choriomeningitis virus become more resistant to apoptosis and acquire enhanced cytokine responsiveness without adjusting their homeostatic proliferation rates; concurrent metabolic adaptations promote increased CD8+ TM quiescence and fitness but also impart the reacquisition of a partial effector-like metabolic profile; and a gradual redistribution of aging CD8+ TM from blood and nonlymphoid tissues to lymphatic organs results in CD8+ TM accumulations in bone marrow, splenic white pulp, and, particularly, lymph nodes. Altogether, these data demonstrate how temporal alterations of fundamental homeostatic determinants converge to render aged CD8+ TM poised for greater recall responses.

The clock is ticking: the impact of ageing on T cell metabolism

“…With regard to memory T cells, increased age led to moderately elevated expression of mTOR and phosphorylated Akt and ribosomal protein S6K in resting memory CD8 T cells . Increased S6K phosphorylation also correlated with an increase in size and granularity of aged compared to young memory T cells .…”

“…Memory‐like populations can be generated during lymphopenia and include CD44 + virtual memory cells that accumulate with age. High spare mitochondrial capacity has been observed in lymphopenia‐induced cells, and similar metabolic adaptations are seen with increasing age in CD44 + CD8 T cells . This suggests that high spare respiratory capacity is uncoupled from antigen experience in T cells.…”

“…Sestrins are thought to have anti‐ageing properties, with the capacity to suppress oxidative stress and regulate AMPK‐mTOR signalling, but sestrin‐mediated T cell dysfunction appears to occur independently of mTOR, through dysregulation of MAPK activation. Of note, senescent memory T cells that have increased basal MAPK activation also exhibit increased basal glycolytic rates . AMPK is also hyperactivated in senescent and aged T cells, possibly as a response to ATP deficit in the cell, which augments basal mitochondrial biogenesis.…”

“…Ageing can augment accumulation of specific subsets by promoting their selective proliferation or differentiation, and also the selective survival of cell subsets. Indeed, a key feature of aged T cells is their augmented survival capacity . Even non‐senescent memory CD8 T cells from aged mice and humans exhibit a survival advantage in vitro after induction of apoptosis .…”

“…Even non‐senescent memory CD8 T cells from aged mice and humans exhibit a survival advantage in vitro after induction of apoptosis . Studies have attributed much of the preferential survival capacity of aged T cells to heightened Bcl‐2 expression . However, increased production of antioxidants such as GSH has been shown to protect aged T cells against oxidative stress and loss of mitochondrial membrane potential, thereby promoting cell survival.…”