Dataset Information

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

ABSTRACT: Cellular senescence is accompanied by a senescence-associated secretory phenotype (SASP). We show here that primary human senescent CD8+ T cells also display a SASP comprising chemokines, cytokines and extracellular matrix remodelling proteases that are unique to this subset and contribute to age-associated inflammation. We found the CD8+ CD45RA+ CD27- EMRA subset to be the most heterogeneous, with a population aligning with the naïve T cells and another with a closer association to the effector memory subset. However, despite the differing processes that give rise to these senescent CD8+ T cells once generated, they both adopt a unique secretory profile with no commonality to any other subset, aligning more closely with senescence than quiescence. Furthermore, we also show that the SASP observed in senescent CD8+ T cells is governed by p38 MAPK signalling.

SUBMITTER: Callender LA

PROVIDER: S-EPMC5770853 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Callender Lauren A LA Carroll Elizabeth C EC Beal Robert W J RWJ Chambers Emma S ES Nourshargh Sussan S Akbar Arne N AN Henson Sian M SM

Aging cell 20171012 1

Cellular senescence is accompanied by a senescence-associated secretory phenotype (SASP). We show here that primary human senescent CD8+ T cells also display a SASP comprising chemokines, cytokines and extracellular matrix remodelling proteases that are unique to this subset and contribute to age-associated inflammation. We found the CD8+ CD45RA+ CD27- EMRA subset to be the most heterogeneous, with a population aligning with the naïve T cells and anoth ...[more]

PMID: 29024417

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Project description:BACKGROUND:Disturbed flow (d-flow)-induced senescence and activation of endothelial cells (ECs) have been suggested to have critical roles in promoting atherosclerosis. Telomeric repeat-binding factor 2 (TERF2)-interacting protein (TERF2IP), a member of the shelterin complex at the telomere, regulates the senescence-associated secretory phenotype (SASP), in which EC activation and senescence are engendered simultaneously by p90RSK-induced phosphorylation of TERF2IP S205 and subsequent nuclear export of the TERF2IP-TERF2 complex. In this study, we investigated TERF2IP-dependent gene expression and its role in regulating d-flow-induced SASP. METHODS:A principal component analysis and hierarchical clustering were used to identify genes whose expression is regulated by TERF2IP in ECs under d-flow conditions. Senescence was determined by reduced telomere length, increased p53 and p21 expression, and increased apoptosis; EC activation was detected by NF-?B activation and the expression of adhesion molecules. The involvement of TERF2IP S205 phosphorylation in d-flow-induced SASP was assessed by depletion of TERF2IP and mutation of the phosphorylation site. RESULTS:Our unbiased transcriptome analysis showed that TERF2IP caused alteration in the expression of a distinct set of genes, including rapamycin-insensitive companion of mTOR (RICTOR) and makorin-1 (MKRN1) ubiquitin E3 ligase, under d-flow conditions. In particular, both depletion of TERF2IP and overexpression of the TERF2IP S205A phosphorylation site mutant in ECs increased the d-flow and p90RSK-induced MKRN1 expression and subsequently inhibited apoptosis, telomere shortening, and NF-?B activation in ECs via suppression of p53, p21, and telomerase (TERT) induction. CONCLUSIONS:MKRN1 and RICTOR belong to a distinct reciprocal gene set that is both negatively and positively regulated by p90RSK. TERF2IP S205 phosphorylation, a downstream event of p90RSK activation, uniquely inhibits MKRN1 expression and contributes to EC activation and senescence, which are key events for atherogenesis.

Dataset Information

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

Publications

Human CD8<sup>+</sup> EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK.

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