p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells

Abstract

T cell senescence is thought to contribute to immune function decline, but the pathways that mediate senescence in these cells are not clear. Here, we evaluated T cell populations from healthy volunteers and determined that human CD8+ effector memory T cells that reexpress the naive T cell marker CD45RA have many characteristics of cellular senescence, including decreased proliferation, defective mitochondrial function, and elevated levels of both ROS and p38 MAPK. Despite their apparent senescent state, we determined that these cells secreted high levels of both TNF-α and IFN-γ and showed potent cytotoxic activity. We found that the senescent CD45RA-expressing population engaged anaerobic glycolysis to generate energy for effector functions. Furthermore, inhibition of p38 MAPK signaling in senescent CD8+ T cells increased their proliferation, telomerase activity, mitochondrial biogenesis, and fitness; however, the extra energy required for these processes did not arise from increased glucose uptake or oxidative phosphorylation. Instead, p38 MAPK blockade in these senescent cells induced an increase in autophagy through enhanced interactions between p38 interacting protein (p38IP) and autophagy protein 9 (ATG9) in an mTOR-independent manner. Together, our findings describe fundamental metabolic requirements of senescent primary human CD8+ T cells and demonstrate that p38 MAPK blockade reverses senescence via an mTOR-independent pathway

Human CD8+EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

“…The authors showed that the MiDAS resulted from an NADH‐AMPK‐p53‐dependent pathway that elicited a SASP but lacked IL‐1‐dependent factors. We have previously shown CD8 + EMRA T cells to display mitochondrial dysfunction (Henson et al ., 2014). Therefore, we investigated whether the CD8 + EMRA SASP was also governed by a p53‐AMPK‐dependent pathway.…”

“…Indeed, we show here that senescent CD8 + T cells exhibited a SASP which differs to that reported for fibroblasts and B and NK cells, in that it is not defined by the expression of IL‐1β and IL‐6. This may relate to our finding that EMRA T cells are unable to phosphorylate mTOR (Henson et al ., 2014), a key molecule in the stabilization and translation of inflammatory cytokine mRNAs (Kafasla et al ., 2014). However, senescent CD8 + T cells do secrete high levels of IL‐18, a pro‐inflammatory cytokine in the IL‐1 family that induces IFN‐γ production.…”

“…T cells that re‐express CD45RA within this subset have multiple characteristics of senescence, including a low proliferative activity, high levels of DNA damage and the loss of telomerase activity (Henson et al ., 2014, 2015). We have also shown that p38 MAPK signalling, which is increased in highly differentiated CD8 + T cells (Henson et al ., 2014), is involved in the loss of telomerase activity and proliferative capacity and that blockade of p38 MAPK activity with a specific small‐molecule inhibitor can restore both proliferation and telomerase activity (Lanna et al ., 2013; Henson et al ., 2014, 2015) in these cells. However, surprisingly the CD45RA‐re‐expressing senescent T cells do not have critically short telomeres (Di Mitri et al ., 2011; Riddell et al ., 2014), suggesting that senescence in these cells may be induced by other mechanisms including DNA damage by increased ROS production (Henson et al ., 2014).…”

“…We have also shown that p38 MAPK signalling, which is increased in highly differentiated CD8 + T cells (Henson et al ., 2014), is involved in the loss of telomerase activity and proliferative capacity and that blockade of p38 MAPK activity with a specific small‐molecule inhibitor can restore both proliferation and telomerase activity (Lanna et al ., 2013; Henson et al ., 2014, 2015) in these cells. However, surprisingly the CD45RA‐re‐expressing senescent T cells do not have critically short telomeres (Di Mitri et al ., 2011; Riddell et al ., 2014), suggesting that senescence in these cells may be induced by other mechanisms including DNA damage by increased ROS production (Henson et al ., 2014). Indeed, we show here that the CD45RA + CD27 − T cells are the most heterogeneous CD8 + T‐cell subset that pertain from either the naïve or effector memory CD8 + T cells, and carry with them hallmarks of each of these subsets.…”

Reduced naïve CD 8 + T ‐cell priming efficacy in elderly adults

“…In particular, elderly individuals harbor a higher proportion of terminally differentiated (CD28 − ) memory CD8 + T‐cells, which exhibit strong effector functions constrained by limited proliferative capabilities in tandem with short telomeres (reviewed in Pawelec et al ., 1999). More recently, Akbar and colleagues have provided new insights into the associated molecular defects (Henson et al ., 2014). However, there is limited information regarding the capacity of old humans to mount primary CD8 + T‐cell responses.…”