DUSP4 deficiency enhances CD25 expression and CD4+ T-cell proliferation without impeding T-cell development.
DUSP4 deficiency enhances CD25 expression and CD4+ T-cell proliferation without impeding T-cell development.
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DOI：
10.1002/eji.201041295
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发表时间：
2012-02
影响因子：
5.4
通讯作者：
Tan, Tse-Hua
中科院分区：
文献类型：
--
作者：
Huang, Ching-Yu;Lin, Yu-Chun;Hsiao, Wan-Yi;Liao, Fang-Hsuean;Huang, Pau-Yi;Tan, Tse-Hua
T细胞的分化和活化受到MAP激酶的关键调节，MAP激酶又受到双特异性磷酸酶（DUSPs）的反馈调节，以确定MAP激酶活化的持续时间和幅度。DUSP 4（也称为MKP 2）是MAP激酶诱导的DUSP成员，其在胸腺细胞分化期间动态表达。我们产生DUSP 4缺陷小鼠以研究DUSP 4在T细胞发育和活化中的功能。我们的研究结果表明，胸腺细胞分化和激活诱导的MAP激酶磷酸化DUSP 4缺陷和野生型小鼠之间是可比的。有趣的是，活化的DUSP 4 −/− CD 4 T细胞过度增殖，而DUSP 4 −/− CD 8 T细胞正常增殖。进一步的机制研究表明，DUSP 4-/-CD 4 T细胞的过度增殖是由于通过增加STAT 5磷酸化而增强的CD 25表达和IL-2信号传导引起的。DUSP 4 −/−小鼠的免疫接种重现了抗原回忆应答中的T细胞过度增殖表型，而Th 1/Th 2极化抗体产生的概况没有改变。综合起来，这些结果表明，其他DUSPs可以弥补DUSP 4在T细胞发育，MAP激酶调节和Th 1/Th 2介导的抗体应答中的缺陷。更重要的是，我们的数据表明，DUSP 4通过STAT 5磷酸化和IL-2信号转导的新调节抑制CD 4 T细胞增殖。
The differentiation and activation of T cells are critically modulated by MAP kinases, which are in turn feed-back regulated by dual-specificity phosphatases (DUSPs) to determine the duration and magnitude of MAP kinase activation. DUSP4 (also known as MKP2) is a MAP kinase-induced DUSP member that is dynamically expressed during thymocyte differentiation. We generated DUSP4-deficient mice to study the function of DUSP4 in T-cell development and activation. Our results showed that thymocyte differentiation and activation-induced MAP kinase phosphorylation were comparable between DUSP4-deficient and wild type mice. Interestingly, activated DUSP4−/− CD4 T cells were hyperproliferative while DUSP4−/− CD8 T cells proliferated normally. Further mechanistic studies suggested that the hyperproliferation of DUSP4−/− CD4 T cells resulted from enhanced CD25 expression and IL-2 signaling through increased STAT5 phosphorylation. Immunization of the DUSP4−/− mice recapitulated the T-cell hyperproliferation phenotype in antigen recall responses, while the profile of Th1/Th2-polarized antibody production was not altered. Combined, these results suggest that other DUSPs may compensate for DUSP4 deficiency in T-cell development, MAP kinase regulation, and Th1/Th2-mediated antibody responses. More importantly, our data indicate that DUSP4 suppress CD4 T-cell proliferation through novel regulations in STAT5 phosphorylation and IL-2 signaling.
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