A sestrin-dependent Erk–Jnk–p38 MAPK activation complex inhibits immunity during aging
Open accessAbstract
Mitogen-activated protein kinases (MAPKs) including Erk, Jnk and p38 regulate diverse cellular functions and are thought to be controlled by independent upstream activation cascades. Here we show that the sestrins bind to and coordinate simultaneous Erk, Jnk and p38 MAPK activation in T lymphocytes within a new immune-inhibitory complex (sestrin-MAPK activation complex (sMAC)). Whereas sestrin ablation resulted in broad reconstitution of immune function in stressed T cells, inhibition of individual MAPKs allowed only partial functional recovery. T cells from old humans (>65 years old) or mice (16-20 months old) were more likely to form the sMAC, and disruption of this complex restored antigen-specific functional responses in these cells. Correspondingly, sestrin deficiency or simultaneous inhibition of all three MAPKs enhanced vaccine responsiveness in old mice. Thus, disruption of sMAC provides a foundation for rejuvenating immunity during aging.
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Senescent T cells in mice and humans both exhibit an increase in phosphorylated γH2Ax subunits in the cytosol as an indicator of increased ATM kinase activity, increased DNA damage, and a DNA-damage senescence phenotype.
“Senescent T cells in mice and humans both exhibit an increase in phosphorylated γH2Ax subunits in the cytosol as an indicator of increased ATM kinase activity, increased DNA damage, and a DNA-damage senescence phenotype [353, 354].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [353]
The Results section (‘Individual MAPKs control distinct aspects of T cell senescence’; page unavailable) reports DNA-damage foci in senescent CD4+ T cells, and the Methods (‘Signaling studies’; page unavailable) list staining for γ-H2A-x. Neither passage establishes increased cytosolic phosphorylated γH2Ax in both mice and humans or identifies it as evidence of increased ATM activity. (LLM, conf=0.86)
Experimental — accuracy not yet measuredP38 inhibits cell cycle progression by activating P53, P21, and P16.
“P38 inhibits cell cycle progression by activating P53, P21, and P16 [64].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [64]
Previous studies on classical CD4 T cell subsets described reduced proliferation, lower IL-2 secretion, and accumulation of metabolic defects, along with higher production of pro-inflammatory mediators.
“For example, previous studies performed on classical CD4 T cell subsets described reduced proliferation, lower secretion of interleukin-2 (IL-2) cytokine (7, 8), and accumulation of metabolic defects (9), along with higher production of pro-inflammatory mediators (10).”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [9]
Knockout of sMAC restored T cell activity (antigen-specific proliferation and cytokine production) from older humans, and enhanced responsiveness to influenza vaccination in aged mice.
“The knockout of sMAC restored T cell activity (antigen-specific proliferation and cytokine production) from older humans, and enhanced responsiveness to influenza vaccination in the aged mice (196).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [196]
Sestrins, the mammalian products of the Sesn1, Sesn2, and Sesn3 genes, are a family of stress sensing proteins.
“Sestrins, the mammalian products of the Sesn1, Sesn2, and Sesn3 genes, are a family of stress sensing proteins (196).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [196]
The authors identified a complex named sestrin-dependent MAPK activation complex (sMAC) that simultaneously coordinates the activation of each MAPK that controls a functional response.
“The authors identified a complex named sestrin-dependent MAPK activation complex (sMAC) that simultaneously coordinates the activation of each MAPK that controls a functional response.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [196]
A block at the level of p38-MAPK by sestrins causes age-related signaling defects in effector and memory CD45RA+/CCR7− T cells.
“For example, a block at the level of p38-MAPK by sestrins causes age-related signaling defects in effector and memory CD45RA+/CCR7− T cells (195, 196).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [196]
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- Authors
- Lanna, A., Gomes, D. C. O., Muller-Durovic, B., McDonnell, T., Escors, D., Gilroy, D. W., Lee, J. H., Karin, M., & Akbar, A. N.
- Affiliations
- University of Oxford (GB)
- University College London (GB)
- Complejo Hospitalario de Navarra (ES)
- University of Michigan (US)
- University of California San Diego (US)
- Corresponding author
- Lanna, Alessio
- Akbar, Arne N
- ORCID
- Venue
- Nature Immunology
- Published
- 2017-01-23
- Volume
- 18
- Issue
- 3
- Pages
- 354-363
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC5321575
- OpenAlex
- W2581238721
- Cited by
- 284
- References
- 39
- Citations by year
- 2026: 16 · 2025: 34 · 2024: 38 · 2023: 23 · 2022: 36 · 2021: 42 · 2020: 48 · 2019: 24 · 2018: 14 · 2017: 9
- FWCI
- 11.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Wellcome Trust (AZR00630, 110229/Z/15/Z)
- Medical Research Council (MR/M003833/1, MR/N017749/1, MR/P00184X/1)
- Biotechnology and Biological Sciences Research Council (BB/L005336/1, BB/E019188/1, BB/J006750/1, BB/L005328/1)
- National Institute on Aging (R21AG045432)
- National Cancer Institute (P01CA128814)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- sestrins, ERK MAPK, JNK MAPK, p38 MAPK, T cells, immunosenescence, MAPK signaling, vaccine response, immune rejuvenation, aged mice
- MeSH terms
- Immunosenescence, Sestrins, Adult, Aged, Aged, 80 and over, Aging, Animals, Cells, Cultured, Female, Heat-Shock Proteins, Humans, Immunity, Male, Middle Aged, Signal Transduction, CD4-Positive T-Lymphocytes, RNA, Small Interfering, Extracellular Signal-Regulated MAP Kinases, MAP Kinase Kinase 4, Mice, Young Adult
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