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

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


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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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


  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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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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