Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1038/ni.2981

Type

Journal article

Journal

Nature immunology

Publication Date

10/2014

Volume

15

Pages

965 - 972

Addresses

Division of Infection and Immunity, University College London, London, UK.

Keywords

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