Article | Published:

A sestrin-dependent Erk–Jnk–p38 MAPK activation complex inhibits immunity during aging

Nature Immunology volume 18, pages 354363 (2017) | Download Citation

Abstract

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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References

  1. 1.

    , & Causes, consequences, and reversal of immune system aging. J. Clin. Invest. 123, 958–965 (2013).

  2. 2.

    , & The ageing immune system: is it ever too old to become young again? Nat. Rev. Immunol. 9, 57–62 (2009).

  3. 3.

    , & The coming acceleration of global population ageing. Nature 451, 716–719 (2008).

  4. 4.

    et al. Reversible senescence in human CD4+CD45RA+CD27 memory T cells. J. Immunol. 187, 2093–2100 (2011).

  5. 5.

    , , & The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat. Immunol. 15, 965–972 (2014).

  6. 6.

    et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J. Clin. Invest. 124, 4004–4016 (2014).

  7. 7.

    et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 18, 1518–1524 (2012).

  8. 8.

    et al. Killer cell lectin-like receptor G1 inhibits NK cell function through activation of adenosine 5′-monophosphate-activated protein kinase. J. Immunol. 197, 2891–2899 (2016).

  9. 9.

    , & Senescence of T lymphocytes: implications for enhancing human immunity. Trends Immunol. 37, 866–876 (2016).

  10. 10.

    , & CD28 T cells: their role in the age-associated decline of immune function. Trends Immunol. 30, 306–312 (2009).

  11. 11.

    & Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001).

  12. 12.

    & Mitogen-activated protein kinase pathways mediated by ERK, Jnk, and p38 protein kinases. Science 298, 1911–1912 (2002).

  13. 13.

    , & MAPK phosphatases—regulating the immune response. Nat. Rev. Immunol. 7, 202–212 (2007).

  14. 14.

    & Function and regulation in MAPK signaling pathways: lessons learned from the yeast Saccharomyces cerevisiae. Biochim. Biophys. Acta 1773, 1311–1340 (2007).

  15. 15.

    et al. Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene 21, 6017–6031 (2002).

  16. 16.

    et al. PA26 is a candidate gene for heterotaxia in humans: identification of a novel PA26-related gene family in human and mouse. Hum. Genet. 112, 573–580 (2003).

  17. 17.

    et al. PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. Oncogene 18, 127–137 (1999).

  18. 18.

    & p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134, 451–460 (2008).

  19. 19.

    , & AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262 (2012).

  20. 20.

    et al. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327, 1223–1228 (2010).

  21. 21.

    et al. Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. Cell Metab. 16, 311–321 (2012).

  22. 22.

    , & Sestrins orchestrate cellular metabolism to attenuate aging. Cell Metab. 18, 792–801 (2013).

  23. 23.

    et al. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 9, 1281–1291 (2014).

  24. 24.

    , & Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell 159, 122–133 (2014).

  25. 25.

    et al. The sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 9, 1–8 (2014).

  26. 26.

    et al. SESN-1 is a positive regulator of lifespan in Caenorhabditis elegans. Exp. Gerontol. 48, 371–379 (2013).

  27. 27.

    et al. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev. Cell 18, 592–604 (2010).

  28. 28.

    p53 strikes mTORC1 by employing sestrins. Cell Metab. 8, 184–185 (2008).

  29. 29.

    et al. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J. Biol. Chem. 282, 32549–32560 (2007).

  30. 30.

    et al. IFN-α inhibits telomerase in human CD8+ T cells by both hTERT downregulation and induction of p38 MAPK signaling. J. Immunol. 191, 3744–3752 (2013).

  31. 31.

    et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N. Engl. J. Med. 352, 2271–2284 (2005).

  32. 32.

    Immune senescence and vaccines to prevent herpes zoster in older persons. Curr. Opin. Immunol. 24, 494–500 (2012).

  33. 33.

    et al. TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 41, 478–492 (2014).

  34. 34.

    , & mTOR is a key modulator of ageing and age-related disease. Nature 493, 338–345 (2013).

  35. 35.

    et al. Scaffold protein Dlgh1 coordinates alternative p38 kinase activation, directing T cell receptor signals toward NFAT but not NF-kappaB transcription factors. Nat. Immunol. 8, 154–161 (2007).

  36. 36.

    The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat. Rev. Immunol. 6, 532–540 (2006).

  37. 37.

    & Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289–295 (2011).

  38. 38.

    et al. Targeting dendritic cell signaling to regulate the response to immunization. Blood 111, 3050–3061 (2008).

  39. 39.

    et al. The loss of telomerase activity in highly differentiated CD8+CD28CD27 T cells is associated with decreased Akt (Ser473) phosphorylation. J. Immunol. 178, 7710–7719 (2007).

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Acknowledgements

We thank A. Sewell, D. Mosser and O. Franzese for discussions. Supported by the Wellcome Trust (AZR00630 to A.L.) and the Biotechnology and Biological Science Research Council (BB/L005328/1 to A.N.A.). D.C.O.G. was supported by the Coordination for the Improvement of Higher Education Personnel (CAPES- Brazil) (grant number 99999.006198/2014-07). B.M.-D. was supported by the Swiss National Foundation (P300PB_161092 and P2BSP3_151877); T.M.D. was supported by an NIHR BRC grant; D.E. was supported by a Miguel Servet Fellowship (CP12/03114) and a FIS project (PI14/00579) from the Instituto de Salud Carlos III, Spain. Mouse Sestrin 1 studies were supported by the Ellison Medical Foundation (AG-SS-2440-10 to M.K.) and the NIH (R21AG045432 to J.H.L.). A.L. is a recipient of a Sir Henry Wellcome Trust Fellowship sponsored by M.L. Dustin (University of Oxford).

Author information

Affiliations

  1. Division of Infection and Immunity, University College London, London, UK.

    • Alessio Lanna
    • , Daniel C O Gomes
    • , Bojana Muller-Durovic
    • , Thomas McDonnell
    • , David Escors
    •  & Arne N Akbar
  2. Nuffield Department of Medicine, University of Oxford, Oxford, UK.

    • Alessio Lanna
  3. Núcleo de Doenças Infecciosas/Núcleo de Biotecnologia, Universidade Federal do Espírito Santo - UFES, Vitória, Brazil.

    • Daniel C O Gomes
  4. Navarrabiomed-Biomedical Research Centre, Fundación Miguel Servet, IdisNA, Complejo Hospitalario de Navarra, Pamplona, Spain.

    • David Escors
  5. Division of Medicine, University College London, London, London, UK.

    • Derek W Gilroy
  6. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.

    • Jun Hee Lee
  7. Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego School of Medicine, La Jolla, California, USA.

    • Michael Karin

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Contributions

A.L. conceived, planned and performed the study, analyzed and interpreted data and wrote the paper; D.C.O.G., B.M.-D. and T.M. performed experiments; D.E. provided lentiviral tools; D.W.G. supported mouse experiments; J.H.L. and M.K. provided Sesn1−/− mice and experimental advice and edited the paper; A.N.A. provided overall guidance, experimental advice and laboratory infrastructure and edited the paper; all authors read and approved the final manuscript.

Competing interests

A.L. and A.N.A. have filed a patent on ‘modulators of sestrins’ for immunotherapy (filing number PCT/IB2016/057209; filing date 30 November 2016) and are founders and equal shareholders of Rejuviron Ltd., which aims to identify and commercialize the use of sestrin inhibitors to boost immunity during aging.

Corresponding authors

Correspondence to Alessio Lanna or Arne N Akbar.

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DOI

https://doi.org/10.1038/ni.3665

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