The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells

p38 phosphorylation occurs downstream of ATM and ROS through TAB1/AMPK activation rather than TCR signaling.

“p38 phosphorylation occurs downstream of ATM and ROS through TAB1/AMPK activation rather than TCR signaling”

Using small molecule inhibitors or specific inhibitory shRNA, p38 inhibition reconstituted proliferation and telomerase activity in T cells after activation.

“Using small molecule inhibitors [23, 30] or specific inhibitory shRNA [24] it was found that p38 inhibition reconstituted proliferation and also telomerase activity in T cells after activation.”

Two separate pathways for p38 MAPK activation in T cells had been previously described.

“Two separate pathways for p38 MAPK activation in T cells had been previously described [24, 60].”

Based on in vitro data, blocking agents to p38 could be used in vivo to enhance certain T cell functions.

“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] .”

A third p38 activation pathway in T cells involves activation of a molecular complex containing AMP-responsive protein kinase (AMPK), the scaffold molecule TAB1 and p38 itself.

“This third p38 activation pathway in T cells was identified recently and involved the activation of a molecular complex that contains AMP-responsive protein kinase (AMPK), a low nutrient and energy sensor, a scaffold molecule TAB 1 and p38 itself [24] (Fig. 2).”

There is a convergence of senescence and nutrient sensing pathways in T cells to activate p38 via AMPK/TAB1.

“This suggests that there is a convergence of senescence and nutrient sensing pathways in T cells to activate p38 via AMPK/TAB1.”

Senescent T cells lose expression of costimulatory receptors CD27 and CD28 that activate the canonical pathway and do not express upstream kinases associated with the canonical pathway, suggesting that p38 may be activated by an alternative mechanism in these cells.

“However senescent T cells lose expression of costimulatory receptors such as CD27 and CD28 that activate the canonical pathway nor do they express the upstream kinases associated with the canonical pathway suggesting that p38 may be activated an alternative mechanism in these cells [24, 60].”

Inhibition of either AMPK, TAB1 or p38 itself reconstitutes proliferation as well as telomerase activity in the senescent T cell population.

“Correspondingly, the inhibition of either AMPK, TAB1 or p38 itself reconstitutes proliferation as well as telomerase activity in the senescent T cell population [24].”

The AMPK/TAB1/p38 complex induces p38 activation through auto-phosphorylation.

“This complex induces p38 activation through auto-phosphorylation.”

Senescent T cells do not express several kinases and scaffold molecules involved in the alternative p38 activation pathway and are unlikely to engage this second pathway for p38 activation.

“However, it was found that senescent T cells do not express several kinases and scaffold molecules that are involved in this alternative p38 activation pathway and are thus unlikely to engage this second pathway for p38 activation [24, 60].”

AMPK is activated not only by sensing low intracellular glucose but also by endogenous DNA damage (senescence) signalling in T cells.

“The critical point is that AMPK is not only activated by sensing low intracellular glucose but also by endogenous DNA damage (senescence) signalling in T cells but also by [24].”

Inhibition of AMPK, TAB1 or p38 provides points for intervention to enhance the function of senescent T cells.

“This provides points for intervention, in addition to targeting p38 itself, to enhance the function of senescent T cells.”

A supramolecular complex containing AMPK, TAB1 and p38 is involved in regulating the function of senescent T cells.

“a supramolecular complex containing AMPK, TAB1 and p38 is involved in regulating the function of senescent T cells”

There are at least three different p38 activation pathways in T cells: canonical, alternative, and the recently identified AMPK/TAB1 mode.

“The existence of at least three different p38 activation pathways in T cells ('Canonical', 'Alternative' and the recently identified AMPK/TAB1 mode)”

Senescence and nutrient sensing signals converge to activate AMPK.

“Since senescence and nutrient sensing signals converge to activate AMPK [24]”

TAB1 is required for p38 activation in senescent cells.

“the scaffold molecule TAB1 required for p38 activation in senescent cells”

p38 is activated through an AMPK/TAB1-dependent pathway in senescent T cells.

“Since p38 is activated through an AMPK/TAB1 dependent pathway in senescent T cells [24]”

AMPK activation strongly inhibits effector T cell responses.

“However, AMPK activation also strongly inhibits effector T cell responses [24].”

Senescent T cells engage a distinct mechanism whereby under low nutrient conditions p38 is phosphorylated via AMPK and the scaffold protein TAB1β, an isoform only expressed in senescent T cells.

“senescent T cells have an engage a distinct mechanism, whereby under low nutrient conditions p38 is phosphorylated via AMPK and the scaffold protein TAB1β, an isoform only expressed in senescent T cells.”

Due to the lifelong and chronic exposure to pathogens, T cells replicate several times and become late-differentiated effector memory T cells with features of replicative senescence.

“Due to the lifelong and chronic exposure to pathogens, T cells replicate several times and become late-differentiated effector memory T cells with features of replicative senescence (38).”

Autophagy, by inhibiting cell senescence, is a critical regulator of memory CD8+ formation, and age-related autophagy defect is one explanation why CD8+ T memory formation becomes defective in old age.

“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).”

This pathway can inhibit telomerase activity, T cell proliferation, and expression of key components of the TCR signalosome.

“This pathway can inhibit telomerase activity, T cell proliferation, and expression of key components of the TCR signalosome.”

Senescent human CD27−/CD28−/CD4+ T cells trigger AMPK to stimulate p38 recruitment, causing p38 auto-phosphorylation mediated by the protein scaffold TAB1.

“In turn, senescent human CD27−/CD28−/CD4+ T cells trigger AMPK to stimulate p38 recruitment, causing p38 auto-phosphorylation mediated by the protein scaffold TAB1.”

In the presence of low-nutrient levels and DNA-damage signaling, the proliferative defect of senescent T cells is reversed by blocking AMPK-TAB1-dependent p38 activation.

“In the presence of low-nutrient levels and DNA-damage signaling the proliferative defect of senescent T cells is reversed by blocking AMPK-TAB1-dependent p38 activation (38).”