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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.

Original publication

DOI

10.1038/ni.3665

Type

Journal article

Journal

Nature immunology

Publication Date

03/2017

Volume

18

Pages

354 - 363

Addresses

Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Keywords

CD4-Positive T-Lymphocytes, Cells, Cultured, Animals, Humans, Mice, MAP Kinase Kinase 4, Extracellular Signal-Regulated MAP Kinases, Heat-Shock Proteins, RNA, Small Interfering, Signal Transduction, Immunity, Aging, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Young Adult, Immunosenescence