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

In the citing paper

“T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species.”

In the citing paper

“Moreover, aging T cells preferentially employ anaerobic glycolysis to generate energy, which results in mitochondrial dysfunction and increased reactive oxygen species (ROS) generation [36].”

In the citing paper

“Within primary human T cells, in both CD4 + [23, 28, 29] and CD8 + [25, 30] populations, there is a subset of poorly proliferative cells that exhibit characteristics that are very similar to senescent fibroblasts (Fig. 1).”

In the citing paper

“An important observation is that T cells within both CD4 + and CD8 + compartments that have senescent characteristics increase during ageing [25, 33-38] and are therefore likely to have an impact on altered immune function in older individuals.”

In the citing paper

“An important observation is that T cells within both CD4 + and CD8 + compartments that have senescent characteristics increase during ageing [25, 33-38] and are therefore likely to have an impact on altered immune function in older individuals.”

In the citing paper

“The highly differentiated CD27 - CD28 - population of T cells can be further divided and the cells that re-express CD45RA within this subset have multiple characteristics of senescence including loss of telomerase activity, DNA damage, high levels of reactive oxygen species (ROS) and the lowest proliferative capacity [25, 30].”

In the citing paper

“Intriguingly, the CD45RA re-expressing senesecent T cells do not have critically short telomeres suggesting that senescence in these cell may be induced by other mechanisms including DNA damage by increased ROS production [25, 30].”

In the citing paper

“It was found that the p38 signalling inhibited autophagy in senescent T cells, a non-canonical mTORC1 independent process, that occurs instead via a mechanism that involved increased trafficking of the autophagy regulating protein Atg9 from the endosomes to the lysosomes [25].”

In the citing paper

“Senescent CD8 + T cells exhibit mitochondrial dysfunction, increased production of reactive oxygen species (ROS) and impaired mitochondrial biogenesis, which may explain their dependence on glycolysis for energy [25].”

In the citing paper

“However despite the increased mitochondrial function, senescent T cells still preferentially utilize glycolysis and not OXPHOS for increased proliferation after p38 blockade.”

In the citing paper

“Blocking p38 enhanced autophagy, increased mitochondrial biogenesis, cleared dysfunctional mitochondria and reduced ROS production in senescent CD8 + T cells [25] indicating an overall improvement of mitochondrial fitness.”

In the citing paper

“Nevertheless, the defective autophagy results in a failure to clear the large giant dysfunctional mitochondria that is linked to increased ROS production by senescent CD8 + T cells [25].”

In the citing paper

“However senescent CD8 + T cells displayed both low autophagic activity [25, 65] and also lack mTORC1 activity [25].”

In the citing paper

“One target for reversing senescence in T cells would be the p38 MAP kinase pathway and based on data that has been obtained in vitro , blocking agents to p38 could be used in vivo to enhance certain T cell functions [23-25, 30] .”

In the citing paper

“The lack of mitochondrial biogenesis may well be a consequence of the failure of senescent T cells to activate mTOR (mammaliam target of rapamycin), a central integrator of immune signalling and cell metabolism [62], as demonstrated by their inability to phosphorylate the mTOCR1 [25] or the mTORC2 complex [63].”

In the citing paper

“Furthermore, the recycling of metabolic precursors resulting from increased autophagy and not greater glucose uptake fuels the enhanced proliferative activity of senescent T cells after p38 inhibition.”

In the citing paper

“It was shown that human senescent CD8 + T cells preferentially utilise glycolysis to generate ATP, as opposed to the effector memory subset which are much more metabolically flexible and can either glycolysis or oxidative phosphorylation (OXPHOS) for functional activities (Fig. 3).”

In the citing paper

“the new awareness of the interrelationship between senescence, nutrition and inflammation in regulating T cell function [25, 29, 61].”

In the citing paper

“The p38-MAPK pathway plays a pleiotropic role in cell survival, both sustaining proliferation, and inducing apoptosis in a cell type-specific manner, depending on the type of stimulus (185).”

In the citing paper

“Autophagy, by inhibiting cell senescence, is a critical regulator of memory CD8+ formation, and age-related autophagy defect is one of the explanations why CD8+ T memory formation becomes defective in old age (38, 185).”

In the citing paper

“Moreover, in senescent CD8+ T cells, p38-MAPK induces an increase in autophagy through interactions between a p38 interacting protein and autophagy protein 9, in a mTOR-independent manner, suggesting that p38-MAPK blockade reverses senescence via mTOR-independent pathway (185).”

In the citing paper

“and high levels of reactive oxygen species in T cells impair cytotoxicity, perhaps mediated by T cell lipid peroxidation, resulting in failure to control viruses (Henson et al. 2014; Matsushita et al. 2015).”