Functional Involvement of Dual Specificity Phosphatase 16 (DUSP16), a c-Jun N-terminal Kinase-specific Phosphatase, in the Regulation of T Helper Cell Differentiation
Functional Involvement of Dual Specificity Phosphatase 16 (DUSP16), a c-Jun N-terminal Kinase-specific Phosphatase, in the Regulation of T Helper Cell Differentiation
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DOI：
10.1074/jbc.m111.245019
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发表时间：
2011-07-15
影响因子：
4.8
通讯作者：
Matsuguchi, Tetsuya
中科院分区：
文献类型：
--
作者：
Musikacharoen, Tipayaratn;Bandow, Kenjiro;Matsuguchi, Tetsuya
当遇到呈递的外源抗原时，初始CD 4（+）Th辅助（Th）细胞分化成表达不同细胞因子组的效应细胞（Th 1、Th 2、Th 17和诱导的调节性T细胞（iTreg））的不同亚群。Th 1/Th 2平衡对于以下免疫应答的性质至关重要。以往的研究表明c-Jun N-末端激酶（JNK）在Th 1/Th 2平衡中起重要作用，但其在Th细胞中的调节机制尚未阐明。在这里，我们表明，双特异性磷酸酶16（DUSP 16，也称为MKP-M或MKP-7），它优先灭活JNK，选择性地表达在Th 2细胞。在初始CD 4（+）细胞的体外分化试验中，DUSP 16表达在Th 2分化期间上调，在Th 1分化期间下调。染色质免疫沉淀显示，在Th 2条件下，CD 4（+）T细胞中dusp 16基因启动子处组蛋白H3/H4的乙酰化增加。用腺病毒转导DUSP 16的幼稚CD 4（+）T细胞导致Th 2中IL-4和加塔-3的mRNA表达增加，而Th 1分化中IFN γ和T-bet的表达降低。相反，转导显性阴性形式的DUSP 16具有相反的效果。此外，在免疫后，T细胞特异性dusp 16转基因小鼠产生的抗原特异性IgG 2a的量较低，而DN dusp 16转基因小鼠产生的抗原特异性IgG 2a的量较高，伴随着抗原特异性IgG 1和IgE的量比对照小鼠减少。总之，这些数据表明DUSP 16在Th 1/Th 2平衡中的功能作用。
Naive CD4(+) Thelper (Th) cells differentiate into distinct subsets of effector cells (Th1, Th2, Th17, and induced regulatory T cells (iTreg)) expressing different sets of cytokines upon encounter with presented foreign antigens. It has been well established that Th1/Th2 balance is critical for the nature of the following immune responses. Previous reports have demonstrated important roles of c-Jun N-terminal kinase (JNK) in Th1/Th2 balance, whereas the regulatory mechanisms of JNK activity in Th cells have not been elucidated. Here, we show that dual specificity phosphatase 16 (DUSP16, also referred to as MKP-M or MKP-7), which preferentially inactivates JNK, is selectively expressed in Th2 cells. In the in vitro differentiation assay of naive CD4(+) cells, DUSP16 expression is up-regulated during Th2 differentiation and down-regulated during Th1 differentiation. Chromatin immunoprecipitation revealed the increased acetylation of histone H3/H4 at the dusp16 gene promoter in CD4(+) T cells under the Th2 condition. Adenoviral transduction of naive CD4(+) T cells with DUSP16 resulted in increased mRNA expression of IL-4 and GATA-3 in Th2 and decreased expression of IFN gamma and T-bet in Th1 differentiation. In contrast, transduction of a dominant negative form of DUSP16 had the reverse effects. Furthermore, upon immunization, T cell-specific dusp16 transgenic mice produced antigen-specific IgG2a at lower amounts, whereas DN dusp16 transgenic mice produced higher amounts of antigen-specific IgG2a accompanied by decreased amounts of antigen-specific IgG1 and IgE than those of control mice. Together, these data suggest the functional role of DUSP16 in Th1/Th2 balance.