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

Nat Immunol. 2014 Oct;15(10):965-72. doi: 10.1038/ni.2981. Epub 2014 Aug 24.


In T lymphocytes, the mitogen-activated protein kinase (MAPK) p38 regulates pleiotropic functions and is activated by canonical MAPK signaling or the alternative activation pathway downstream of the T cell antigen receptor (TCR). Here we found that senescent human T cells lacked the canonical and alternative pathways for the activation of p38 but spontaneously engaged the metabolic master regulator AMPK to trigger recruitment of p38 to the scaffold protein TAB1, which caused autophosphorylation of p38. Signaling via this pathway inhibited telomerase activity, T cell proliferation and the expression of key components of the TCR signalosome. Our findings identify a previously unrecognized mode for the activation of p38 in T cells driven by intracellular changes such as low-nutrient and DNA-damage signaling (an 'intrasensory' pathway). The proliferative defect of senescent T cells was reversed by blockade of AMPK-TAB1-dependent activation of p38.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / immunology*
  • AMP-Activated Protein Kinases / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Aged
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Cellular Senescence / genetics
  • Cellular Senescence / immunology
  • Enzyme Activation / immunology
  • Female
  • Gene Expression / immunology
  • Humans
  • Immunoblotting
  • Male
  • Middle Aged
  • Phosphorylation / immunology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Telomerase / genetics
  • Telomerase / immunology
  • Telomerase / metabolism
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / immunology*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Adaptor Proteins, Signal Transducing
  • TAB1 protein, human
  • p38 Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases
  • TERT protein, human
  • Telomerase