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

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 co-ordinate 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 only allowed partial functional recovery. T cells from old humans and mice 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 ageing.

Functional systemic CD 4 immunity is required for clinical responses to PD ‐L1/ PD ‐1 blockade therapy

“…The majority of CD4 T HD cells were central‐memory (CD45RA negative CD62L + ) and effector‐memory (CD45RA negative CD62L negative ) cells, without differences between G1 and G2 cohorts. Increased genotoxic damage is strongly associated with T‐cell senescence and can be evaluated by H2AX expression (Lanna et al , ). Interestingly, NSCLC CD4 T cells exhibited extensive genotoxic damage in both T HD and non‐T HD subsets without differences between G1 and G2 patient cohorts, unlike T cells from age‐matched healthy donors (Fig EV4B).…”

“…Human T cells undergo a natural differentiation process following the initial antigen recognition, characterized by the progressive loss of CD27 and CD28 surface expression, and acquisition of memory and effector functions (Lanna et al , , ). Hence, human T cells can be classified according to their CD27/CD28 expression profiles into poorly differentiated (CD27 + CD28 + ), intermediately differentiated (CD27 negative CD28 + ), and highly differentiated (CD27 negative CD28 low/negative , T HD ) subsets (Lanna et al , ).…”

Recent Insights into the Biological Functions of Sestrins in Health and Disease

“…The expression of Sesn1, Sesn2 and Sesn3 were all higher in human senescent CD4+ T cells from young donors than that in nonsenescent and intermediate CD4+ T cells. Besides, inhibition of Sesn1, Sesn2 and Sesn3 in senescent T cells showed broad functional reversal of senescence, apparent as enhancement of cell proliferation [74]. Mechanically, they demonstrated that the MAPKs including ERK, JNK and p38, but not mTOR pathway, mediated the pro-senescent function of Sesns in CD4+ T cells through the formation of a new immune-inhibitory complex (Sesn-MAPK activation complex (sMAC)).…”

“…These results were opposite to the well-documented anti-aging properties of Sesns [13, 75, 76], which indicated that the Sesns may exert different functions in T cells. Moreover, they found that 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 [74]. …”

GSK‐3β inhibition protects the rat heart from the lipopolysaccharide‐induced inflammation injury via suppressing FOXO3A activity

“…In addition, ERK and AMPK signalling are two important pathways activated by LPS in many cell types. ERK contributes to the induction of inflammation and apoptosis, whereas AMPK exerts reverse effects in the processes through cross‐talking with NF‐κB . As shown in Figure D‐I, ERK and AMPK signalling were activated by the exposure of CMs to LPS for 15 or 30 minutes.…”