Lack of the T cell-specific alternative p38 activation pathway reduces autoimmunity and inflammation
Lack of the T cell-specific alternative p38 activation pathway reduces autoimmunity and inflammation
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DOI：
10.1182/blood-2011-01-333039
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发表时间：
2011-09-22
期刊：
影响因子：
20.3
通讯作者：
Ashwell, Jonathan D.
中科院分区：
文献类型：
--
作者：
Jirmanova, Ludmila;Torchia, Maria Letizia Giardino;Ashwell, Jonathan D.
通过 T 细胞受体 (TCR) 的刺激，通过 p38 Tyr-323 (p38(Y323)) 的磷酸化激活 p38 α 和 p38 β。在这里，我们描述了 p38 α 和/或 β Tyr-323 已被 Phe 取代的敲入小鼠的特征。我们发现 p38 α 占 TCR 诱导的 p38 激活的三分之二，p38 β 占剩余部分。来自双敲入小鼠 (p38 alpha beta (Y323F)) 的 T 细胞在 TCR 介导的增殖以及 Th1 和 Th17 偏向方面存在缺陷，前者对应于无法维持 T-bet 表达。将 p38 α(Y323F) 引入 Gadd45 α 缺陷小鼠中，其中替代 p38 途径持续活跃，可逆转 T 细胞过度增殖和自身免疫。此外，p38 alpha beta (Y323F) 小鼠延迟了炎症性自身免疫性疾病（胶原诱导的关节炎和实验性自身免疫性脑脊髓炎）的发病并减轻了其严重程度。因此，p38 的 T 细胞特异性选择性激活是 T 细胞增殖、Th 倾斜和炎症自身免疫的重要途径，并且可能是干预这些过程的有吸引力的组织特异性靶标。 （血。2011；118(12):3280-3289）
Stimulation via the T-cell receptor (TCR) activates p38 alpha and p38 beta by phosphorylation of p38 Tyr-323 (p38(Y323)). Here we characterize knockin mice in which p38 alpha and/or beta Tyr-323 has been replaced with Phe. We find that p38 alpha accounts for two-thirds and p38 beta the remainder of TCR-induced p38 activation. T cells from double knockin mice (p38 alpha beta(Y323F)) had defects in TCR-mediated proliferation and Th1 and Th17 skewing, the former corresponding with an inability to sustain T-bet expression. Introduction of p38 alpha(Y323F) into Gadd45 alpha-deficient mice, in which the alternative p38 pathway is constitutively active, reversed T-cell hyperproliferation and autoimmunity. Furthermore, p38 alpha beta(Y323F) mice had delayed onset and reduced severity of the inflammatory autoimmune diseases collagen-induced arthritis and experimental autoimmune encephalomyelitis. Thus, T cell-specific alternative activation of p38 is an important pathway in T-cell proliferation, Th skewing, and inflammatory autoimmunity, and may be an attractive tissue-specific target for intervention in these processes. (Blood. 2011;118(12):3280-3289)