Hayakawa Morisada, Hayakawa Hiroko, Petrova Tsvetana, Ritprajak Patcharee, Sutavani Ruhcha V, Jiménez-Andrade Guillermina Yanek, Sano Yasuyo, Choo Min-Kyung, Seavitt John, Venigalla Ram K C, Otsu Kinya, Georgopoulos Katia, Arthur J Simon C, Park Jin Mo
From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129; the Department of Biochemistry, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
the Division of Cell Signalling and Immunology, School of Life Sciences, Wellcome Trust Building, Dundee DD1 5EH, United Kingdom.
J Biol Chem. 2017 Feb 3;292(5):1762-1772. doi: 10.1074/jbc.M116.764548. Epub 2016 Dec 23.
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.
进化上保守的蛋白激酶p38介导对环境应激和微生物感染的固有抗性。哺乳动物中存在四种p38亚型，它们可能已被用于适应性免疫中的新作用。缺乏p38α（普遍表达的p38亚型）的小鼠T细胞在表达另一种亚型p38β的量增加时，没有明显的细胞自主缺陷。T细胞同时缺乏p38α和p38β的小鼠表现出淋巴萎缩和Foxp3调节性T细胞频率升高。幼稚CD4 T细胞中p38α和p38β的双重缺陷导致T细胞受体参与后MAPK激活的蛋白激酶（MK）依赖性mTOR信号减弱，并在适当的诱导条件下增强它们向调节性T细胞的分化。p38-MK-mTOR信号模块的药理学抑制产生了类似的效果，揭示了治疗应用的潜力。
