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p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells
Open accessAbstract
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.
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In the citing paper
“T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species.”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [36]
In the citing paper
“Moreover, aging T cells preferentially employ anaerobic glycolysis to generate energy, which results in mitochondrial dysfunction and increased reactive oxygen species (ROS) generation [36].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [36]
In the citing paper
“Within primary human T cells, in both CD4 + [23, 28, 29] and CD8 + [25, 30] populations, there is a subset of poorly proliferative cells that exhibit characteristics that are very similar to senescent fibroblasts (Fig. 1).”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“An important observation is that T cells within both CD4 + and CD8 + compartments that have senescent characteristics increase during ageing [25, 33-38] and are therefore likely to have an impact on altered immune function in older individuals.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“An important observation is that T cells within both CD4 + and CD8 + compartments that have senescent characteristics increase during ageing [25, 33-38] and are therefore likely to have an impact on altered immune function in older individuals.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“The highly differentiated CD27 - CD28 - population of T cells can be further divided and the cells that re-express CD45RA within this subset have multiple characteristics of senescence including loss of telomerase activity, DNA damage, high levels of reactive oxygen species (ROS) and the lowest proliferative capacity [25, 30].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“Intriguingly, the CD45RA re-expressing senesecent T cells do not have critically short telomeres suggesting that senescence in these cell may be induced by other mechanisms including DNA damage by increased ROS production [25, 30].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“It was found that the p38 signalling inhibited autophagy in senescent T cells, a non-canonical mTORC1 independent process, that occurs instead via a mechanism that involved increased trafficking of the autophagy regulating protein Atg9 from the endosomes to the lysosomes [25].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“Senescent CD8 + T cells exhibit mitochondrial dysfunction, increased production of reactive oxygen species (ROS) and impaired mitochondrial biogenesis, which may explain their dependence on glycolysis for energy [25].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“However despite the increased mitochondrial function, senescent T cells still preferentially utilize glycolysis and not OXPHOS for increased proliferation after p38 blockade.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“Blocking p38 enhanced autophagy, increased mitochondrial biogenesis, cleared dysfunctional mitochondria and reduced ROS production in senescent CD8 + T cells [25] indicating an overall improvement of mitochondrial fitness.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“Nevertheless, the defective autophagy results in a failure to clear the large giant dysfunctional mitochondria that is linked to increased ROS production by senescent CD8 + T cells [25].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“However senescent CD8 + T cells displayed both low autophagic activity [25, 65] and also lack mTORC1 activity [25].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“One target for reversing senescence in T cells would be the p38 MAP kinase pathway and based on data that has been obtained in vitro , blocking agents to p38 could be used in vivo to enhance certain T cell functions [23-25, 30] .”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“The lack of mitochondrial biogenesis may well be a consequence of the failure of senescent T cells to activate mTOR (mammaliam target of rapamycin), a central integrator of immune signalling and cell metabolism [62], as demonstrated by their inability to phosphorylate the mTOCR1 [25] or the mTORC2 complex [63].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“Furthermore, the recycling of metabolic precursors resulting from increased autophagy and not greater glucose uptake fuels the enhanced proliferative activity of senescent T cells after p38 inhibition.”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“It was shown that human senescent CD8 + T cells preferentially utilise glycolysis to generate ATP, as opposed to the effector memory subset which are much more metabolically flexible and can either glycolysis or oxidative phosphorylation (OXPHOS) for functional activities (Fig. 3).”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“the new awareness of the interrelationship between senescence, nutrition and inflammation in regulating T cell function [25, 29, 61].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [25]
In the citing paper
“The p38-MAPK pathway plays a pleiotropic role in cell survival, both sustaining proliferation, and inducing apoptosis in a cell type-specific manner, depending on the type of stimulus (185).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [185]
In the citing paper
“Autophagy, by inhibiting cell senescence, is a critical regulator of memory CD8+ formation, and age-related autophagy defect is one of the explanations why CD8+ T memory formation becomes defective in old age (38, 185).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [185]
In the citing paper
“Moreover, in senescent CD8+ T cells, p38-MAPK induces an increase in autophagy through interactions between a p38 interacting protein and autophagy protein 9, in a mTOR-independent manner, suggesting that p38-MAPK blockade reverses senescence via mTOR-independent pathway (185).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [185]
In the citing paper
“and high levels of reactive oxygen species in T cells impair cytotoxicity, perhaps mediated by T cell lipid peroxidation, resulting in failure to control viruses (Henson et al. 2014; Matsushita et al. 2015).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Henson et al. 2014
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“Furthermore, aged memory CD8 T cells may have increased mTOR activity and glycolysis well as a reduced ability to engage in autophagy (Davenport et al., 2019; Henson et al., 2014), while newly activated aged CD4 T cells fail to”
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Metadata
- Authors
- Henson, S. M., Lanna, A., Riddell, N. E., Franzese, O., Macaulay, R., Griffiths, S. J., Puleston, D. J., Watson, A. S., Simon, A. K., Tooze, S. A., & Akbar, A. N.
- Affiliations
- University College London (GB)
- University of Rome Tor Vergata (IT)
- University of Oxford (GB)
- Cancer Research UK (GB)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-08-01
- Volume
- 124
- Issue
- 9
- Pages
- 4004-4016
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4151208
- OpenAlex
- W1976615668
- Cited by
- 389
- References
- 60
- Citations by year
- 2026: 29 · 2025: 49 · 2024: 42 · 2023: 33 · 2022: 37 · 2021: 39 · 2020: 28 · 2019: 31 · 2018: 27 · 2017: 27 · 2016: 32 · 2015: 13 · 2014: 2
- FWCI
- 16.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- Cancer Research UK (15153)
- National Institute for Health and Care Research
- University College London
- Directorate for Biological Sciences
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (BB/J006750/1, BB/G021422/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- T cell senescence, CD8+ T cells, p38 MAPK signaling, mTOR-independent autophagy, Atg9, CD45RA, effector memory T cells, mitochondrial biogenesis, anaerobic glycolysis, telomerase activity, cytotoxicity, immunosenescence, T cell metabolism
- MeSH terms
- Autophagy-Related Proteins, Mechanistic Target of Rapamycin Complex 1, Adult, Autophagy, DNA Damage, Glycolysis, Humans, Membrane Proteins, Mitochondria, Oxidative Phosphorylation, Cellular Senescence, CD8-Positive T-Lymphocytes, MAP Kinase Signaling System, Vesicular Transport Proteins, Multiprotein Complexes, p38 Mitogen-Activated Protein Kinases, Membrane Potential, Mitochondrial, TOR Serine-Threonine Kinases
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