Journal
NATURE IMMUNOLOGY
Volume 18, Issue 3, Pages 354-363Publisher
NATURE PORTFOLIO
DOI: 10.1038/ni.3665
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Funding
- Wellcome Trust [AZR00630]
- Biotechnology and Biological Science Research Council [BB/L005328/1]
- Coordination for the Improvement of Higher Education Personnel (CAPES Brazil) [99999.006198/2014-07]
- Swiss National Foundation [P300PB_161092, P2BSP3_151877]
- NIHR BRC
- Miguel Servet Fellowship [CP12/03114]
- FIS project from the Instituto de Salud Carlos III, Spain [PI14/00579]
- Ellison Medical Foundation [AG-SS-2440-10]
- NIH [R21AG045432]
- M.L. Dustin (University of Oxford)
- Swiss National Science Foundation (SNF) [P2BSP3_151877, P300PB_161092] Funding Source: Swiss National Science Foundation (SNF)
- BBSRC [BB/E019188/1, BB/L005336/1, BB/J006750/1, BB/L005328/1] Funding Source: UKRI
- MRC [MR/P00184X/1, MR/N017749/1, MR/M003833/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L005336/1, BB/J006750/1, BB/E019188/1] Funding Source: researchfish
- Medical Research Council [MR/N017749/1, MR/M003833/1, MR/P00184X/1] Funding Source: researchfish
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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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