Loss of Functionally Redundant p38 Isoforms in T Cells Enhances Regulatory T Cell Induction.
Loss of Functionally Redundant p38 Isoforms in T Cells Enhances Regulatory T Cell Induction.
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DOI：
10.1074/jbc.m116.764548
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发表时间：
2017-02-03
期刊：
影响因子：
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通讯作者：
Park JM
中科院分区：
文献类型：
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作者：
Hayakawa M;Hayakawa H;Petrova T;Ritprajak P;Sutavani RV;Jiménez-Andrade GY;Sano Y;Choo MK;Seavitt J;Venigalla RKC;Otsu K;Georgopoulos K;Arthur JSC;Park JM
进化上保守的蛋白激酶p38介导对环境胁迫和微生物感染的先天抗性。哺乳动物中存在四种p38亚型，可能在适应性免疫中发挥了新的作用。缺乏p38α（普遍表达的p38异构体）的小鼠T细胞，在表达另一种异构体p38β的量升高时，没有表现出明显的细胞自主缺陷。T细胞同时缺乏p38α和p38β的小鼠表现出淋巴样细胞萎缩和Foxp3+调节性T细胞频率升高。naïve CD4+ T细胞中p38α和p38β的双重缺乏导致mapk激活的蛋白激酶（MK）依赖的mTOR信号在T细胞受体参与后减弱，并在适当的诱导条件下增强其向调节性T细胞的分化。药理抑制p38-MK-mTOR信号模块产生类似的效果，揭示了治疗应用的潜力。
The evolutionarily conserved protein kinase p38 mediates innate resistance to environmental stress and microbial infection. Four p38 isoforms exist in mammals and may have been co-opted for new roles in adaptive immunity. Murine T cells deficient in p38α, the ubiquitously expressed p38 isoform, showed no readily apparent cell-autonomous defects while expressing elevated amounts of another isoform, p38β. Mice with T cells simultaneously lacking p38α and p38β displayed lymphoid atrophy and elevated Foxp3+ regulatory T cell frequencies. Double deficiency of p38α and p38β in naïve CD4+ T cells resulted in an attenuation of MAPK-activated protein kinase (MK)-dependent mTOR signaling after T cell receptor engagement, and enhanced their differentiation into regulatory T cells under appropriate inducing conditions. Pharmacological inhibition of the p38-MK-mTOR signaling module produced similar effects, revealing potential for therapeutic applications.