Defective induction of the proteasome associated with T-cell receptor signaling underlies T-cell senescence
Defective induction of the proteasome associated with T-cell receptor signaling underlies T-cell senescence
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DOI：
10.1111/gtc.12728
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发表时间：
2019-11-06
期刊：
影响因子：
2.1
通讯作者：
Murata, Shigeo
中科院分区：
文献类型：
--
作者：
Arata, Yoshiyuki;Watanabe, Ayaka;Murata, Shigeo
蛋白酶体降解机制对于包括衰老和T细胞免疫在内的多种细胞过程是必不可少的。蛋白酶体活性降低与衰老过程有关;然而，CD 4（+）T细胞中蛋白酶体的调节与衰老的关系尚不清楚。在这里，我们表明，缺陷的诱导蛋白酶体在CD 4（+）T细胞的T细胞受体（TCR）刺激T细胞衰老的基础。蛋白酶体功能障碍促进衰老相关表型，包括增殖缺陷、细胞因子产生和PD-1（+）CD 44（高）CD 4（+）T细胞水平升高。TCR信号传导通过MEK-、IKK-和钙调神经磷酸酶依赖性途径诱导的蛋白酶体随着年龄的增长而减弱，并且在PD-1（+）CD 44（高）CD 4（+）T细胞中减少，其比例随着年龄的增长而增加。我们的研究结果表明，蛋白酶体的诱导缺陷是CD 4（+）T细胞衰老的标志。
The proteasome degradation machinery is essential for a variety of cellular processes including senescence and T-cell immunity. Decreased proteasome activity is associated with the aging process; however, the regulation of the proteasome in CD4(+) T cells in relation to aging is unclear. Here, we show that defects in the induction of the proteasome in CD4(+) T cells upon T-cell receptor (TCR) stimulation underlie T-cell senescence. Proteasome dysfunction promotes senescence-associated phenotypes, including defective proliferation, cytokine production and increased levels of PD-1(+) CD44(High) CD4(+) T cells. Proteasome induction by TCR signaling via MEK-, IKK- and calcineurin-dependent pathways is attenuated with age and decreased in PD-1(+) CD44(High) CD4(+) T cells, the proportion of which increases with age. Our results indicate that defective induction of the proteasome is a hallmark of CD4(+) T-cell senescence.