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p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells

Henson, SM, Lanna, A, Riddell, N, Franzese, O, Macaulay, R, Griffiths, SJ, Puleston, DJ, Watson, AS, Simon, AK, Tooze, SA and Akbar, AN (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells Journal of Clinical Investigation, 124 (9). pp. 4004-4016.

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Abstract

T cell senescence is thought to contribute to immune function decline, but the pathways that mediate senescence in these cells are not clear. Here, we evaluated T cell populations from healthy volunteers and determined that human CD8+ effector memory T cells that reexpress the naive T cell marker CD45RA have many characteristics of cellular senescence, including decreased proliferation, defective mitochondrial function, and elevated levels of both ROS and p38 MAPK. Despite their apparent senescent state, we determined that these cells secreted high levels of both TNF-α and IFN-γ and showed potent cytotoxic activity. We found that the senescent CD45RA-expressing population engaged anaerobic glycolysis to generate energy for effector functions. Furthermore, inhibition of p38 MAPK signaling in senescent CD8+ T cells increased their proliferation, telomerase activity, mitochondrial biogenesis, and fitness; however, the extra energy required for these processes did not arise from increased glucose uptake or oxidative phosphorylation. Instead, p38 MAPK blockade in these senescent cells induced an increase in autophagy through enhanced interactions between p38 interacting protein (p38IP) and autophagy protein 9 (ATG9) in an mTOR-independent manner. Together, our findings describe fundamental metabolic requirements of senescent primary human CD8+ T cells and demonstrate that p38 MAPK blockade reverses senescence via an mTOR-independent pathway.

Item Type: Article
Subjects : Biosciences
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
AuthorsEmailORCID
Henson, SMUNSPECIFIEDUNSPECIFIED
Lanna, AUNSPECIFIEDUNSPECIFIED
Riddell, NUNSPECIFIEDUNSPECIFIED
Franzese, OUNSPECIFIEDUNSPECIFIED
Macaulay, RUNSPECIFIEDUNSPECIFIED
Griffiths, SJUNSPECIFIEDUNSPECIFIED
Puleston, DJUNSPECIFIEDUNSPECIFIED
Watson, ASUNSPECIFIEDUNSPECIFIED
Simon, AKUNSPECIFIEDUNSPECIFIED
Tooze, SAUNSPECIFIEDUNSPECIFIED
Akbar, ANUNSPECIFIEDUNSPECIFIED
Date : 2 September 2014
Funders : Biotechnology and Biological Sciences Research Council (BBSRC), Medical Research Council (MRC)
Identification Number : https://doi.org/10.1172/JCI75051
Copyright Disclaimer : © 2014 American Society for Clinical Investigation. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ or send a letter to Creative Commons, PO Box 1866, Mountain View, CA 94042, USA.
Depositing User : Symplectic Elements
Date Deposited : 13 Mar 2017 15:25
Last Modified : 13 Mar 2017 15:25
URI: http://epubs.surrey.ac.uk/id/eprint/813763

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