Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 9, Pages 4004-4016Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI75051
Keywords
-
Categories
Funding
- Biotechnology and Biological Sciences Research Council
- Medical Research Council
- Oxford Biomedical Research Centre - NIHR
- Wellcome Trust
- Lady Tata Memorial Trust
- Cancer Research UK
- BBSRC [BB/G021422/1, BB/J006750/1] Funding Source: UKRI
- MRC [G9721629, G0900950, G0501446] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J006750/1, BB/G021422/1] Funding Source: researchfish
- Cancer Research UK [15153] Funding Source: researchfish
- Medical Research Council [G0900950B, G0900950, 1068333, G0501446, G9721629, G9721629B] Funding Source: researchfish
Ask authors/readers for more resources
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-alpha and IFN-gamma 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available