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

Abstract

In T lymphocytes, p38 MAP kinase (MAPK) regulates pleiotropic functions and is activated by canonical MAPK signaling or the alternative T cell receptor (TCR) activation pathway. Here we show that senescent human T cells lack the canonical and alternative pathways of p38 activation, but spontaneously engage the metabolic master regulator AMPK to trigger p38 recruitment to the scaffold TAB1 causing p38 auto-phosphorylation. Signaling via this pathway inhibits telomerase activity, T cell proliferation and expression of key components of the TCR signalosome. Our findings identify an unrecognized mode of p38 activation in T cells driven by intracellular changes such as low-nutrient and DNA-damage signaling (‘intra-sensory’ pathway). The proliferative defect of senescent T cells is reversed by blocking AMPK-TAB1-dependent p38 activation.

Aging, cytomegalovirus (CMV) and influenza vaccine responses

“…Signaling through this pathway inhibits telomerase activity, T cell proliferation and the expression of key components of the TCR signaling machinery, and has been proposed to drive the senescence of human T cells. 69 These results are in line with the hypothesis that aging is powerfully influenced by alterations in nutrient sensing and metabolism. 70 Although aging is associated with increased inflammation, [71][72][73][74] increases in the anti-inflammatory response can also occur, and the increased production of IL-10 and the decreased IFN-g:IL-10 ratio in influenza-stimulated lymphocyte cultures has been shown to be associated with reduced cytolytic capacity of CD8C T cells which clear influenza virus from infected lungs.…”

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

“…However, while we found the EMRAs to express the highest level of p‐p53 (Fig. 2A), they, unlike their CD4 + senescent counterparts (Lanna et al ., 2014), did not display any AMPK phosphorylation, either directly ex vivo (Fig. S1B) or following stimulation (Fig.…”

Cellular senescence impact on immune cell fate and function

“…For instance, TNF‐α or IFN‐γ, archetypical inflammatory cytokines, can trigger premature senescence of CD8 + T cells in vitro by activating the stress kinase p38 MAPK and down‐regulating hTERT gene expression (Di Mitri et al ., 2011; Lanna et al ., 2013). Accordingly, pharmacological inhibition of p38 MAPK regulatory pathway such as AMPK–TAB 1 axis delays T‐cell senescence‐induced cell cycle arrest (Lanna et al ., 2014). …”