Reversible Senescence in Human CD4+CD45RA+CD27- Memory T Cells
Reversible Senescence in Human CD4+CD45RA+CD27- Memory T Cells
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DOI：
10.4049/jimmunol.1100978
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发表时间：
2011-09-01
影响因子：
4.4
通讯作者：
Akbar, Arne N.
中科院分区：
文献类型：
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作者：
Di Mitri, Diletta;Azevedo, Rita I.;Akbar, Arne N.
持续的病毒感染和炎症综合征诱导具有终末分化或衰老特征的T细胞聚集。然而，调节这些细胞终末期分化的机制尚不清楚。人CD 4（+）效应记忆（EM）T细胞（CD 27（-）CD 45 RA（-））以及再表达CD 45 RA的EM T细胞（CD 27（-）CD 45 RA（+）; EMRA）具有终末期分化的许多特征。这些包括表面KLRG 1和CD 57的表达，降低的复制能力，降低的存活率，以及TCR活化后核γ H2 AX的高表达。一个矛盾的观察是，尽管CD 4（+）EMRA T细胞在活化后表现出有缺陷的端粒酶活性，但它们具有比中央记忆（CM）样（CD 27（+）CD 45 RA（-））和EM（CD 27（-）CD 45 RA（-））CD 4（+）T细胞显著更长的端粒。这表明端粒酶活性在该人群中被积极抑制。由于促炎细胞因子如TNF-α通过p38 MAPK途径抑制T细胞中的端粒酶活性，我们研究了p38信号在CD 4（+）EMRAT细胞中的参与。我们发现总的和磷酸化的p38在EM和EMRA中的表达最高，与其他CD 4（+）T细胞亚群相比。此外，抑制p38信号，特别是在CD 4（+）EMRAT细胞中，显着提高其端粒酶活性和TCR激活后的存活率。因此，p38 MAPK通路的激活直接参与高度分化的CD 4（+）T细胞的某些衰老特征。特别是，CD 4（+）EMRA T细胞具有端粒非依赖性衰老的特征，其由可逆的活性细胞信号传导途径调节。免疫学杂志，2011，187：2093-2100。
Persistent viral infections and inflammatory syndromes induce the accumulation of T cells with characteristics of terminal differentiation or senescence. However, the mechanism that regulates the end-stage differentiation of these cells is unclear. Human CD4(+) effector memory (EM) T cells (CD27(-)CD45RA(-)) and also EM T cells that re-express CD45RA (CD27(-)CD45RA(+); EMRA) have many characteristics of end-stage differentiation. These include the expression of surface KLRG1 and CD57, reduced replicative capacity, decreased survival, and high expression of nuclear gamma H2AX after TCR activation. A paradoxical observation was that although CD4(+) EMRA T cells exhibit defective telomerase activity after activation, they have significantly longer telomeres than central memory (CM)-like (CD27(+)CD45RA(-)) and EM (CD27(-)CD45RA(-)) CD4(+) T cells. This suggested that telomerase activity was actively inhibited in this population. Because proinflammatory cytokines such as TNF-alpha inhibited telomerase activity in T cells via a p38 MAPK pathway, we investigated the involvement of p38 signaling in CD4(+) EMRAT cells. We found that the expression of both total and phosphorylated p38 was highest in the EM and EMRA compared with that of other CD4(+) T cell subsets. Furthermore, the inhibition of p38 signaling, especially in CD4(+) EMRAT cells, significantly enhanced their telomerase activity and survival after TCR activation. Thus, activation of the p38 MAPK pathway is directly involved in certain senescence characteristics of highly differentiated CD4(+) T cells. In particular, CD4(+) EMRA T cells have features of telomere-independent senescence that are regulated by active cell signaling pathways that are reversible. The Journal of Immunology, 2011, 187: 2093-2100.