Pim-2 Kinase Influences Regulatory T Cell Function and Stability by Mediating Foxp3 Protein N-terminal Phosphorylation
Pim-2 Kinase Influences Regulatory T Cell Function and Stability by Mediating Foxp3 Protein N-terminal Phosphorylation
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DOI：
10.1074/jbc.m115.638221
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发表时间：
2015-08-14
影响因子：
4.8
通讯作者：
Greene, Mark I.
中科院分区：
文献类型：
--
作者：
Deng, Guoping;Nagai, Yasuhiro;Greene, Mark I.
调节免疫反应的程度是保持自我耐受和限制炎症过程的要求。CD4(+)CD25(+)Foxp3(+)调节性T细胞(Treg)发挥调节作用。Foxp3转录因子被认为是Treg细胞发育和功能的主要调节因子。Foxp3功能本身受多种翻译后修饰的直接调节，这些修饰是对各种外部刺激的反应。Foxp3蛋白是几个动态的大分子调节复合体的组成部分。这些复合体随着时间的推移而改变成分，并通过不同的信号来调节调节性T细胞的发育和功能。在这里，我们确定了一种通过离散的磷酸化来调节Foxp3水平和活性的机制。Pim-2激酶可以磷酸化Foxp3，导致Treg细胞抑制功能减弱。Foxp3的氨基末端结构域被Pim-2激酶在多个位点修饰。这种修饰导致与Treg细胞功能相关的蛋白质表达改变，并增加Treg细胞谱系的稳定性。Treg细胞抑制功能可以通过药物抑制Pim-2激酶活性或通过基因敲除啮齿动物Treg细胞中的Pim-2来上调。在体内，Pim-2活性的缺乏增加了宿主对葡聚糖硫酸钠诱导的结肠炎的抵抗力，Pim-2小分子激酶抑制剂也改变了Treg细胞的功能。我们的研究定义了一条限制Foxp3功能调节的途径，因为Pim-2激酶代表了一个潜在的治疗靶点，用于调节Treg细胞在控制免疫反应中的抑制活性。
Regulation of the extent of immune responses is a requirement to maintain self-tolerance and limit inflammatory processes. CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells play a role in regulation. The Foxp3 transcription factor is considered a dominant regulator for Treg cell development and function. Foxp3 function itself is directly regulated by multiple post-translational modifications that occur in response to various external stimuli. The Foxp3 protein is a component of several dynamic macromolecular regulatory complexes. The complexes change constituents over time and through different signals to regulate the development and function of regulatory T cells. Here we identified a mechanism regulating Foxp3 level and activity that operates through discrete phosphorylation. The Pim-2 kinase can phosphorylate Foxp3, leading to decreased suppressive functions of Treg cells. The amino-terminal domain of Foxp3 is modified at several sites by Pim-2 kinase. This modification leads to altered expression of proteins related to Treg cell functions and increased Treg cell lineage stability. Treg cell suppressive function can be up-regulated by either pharmacologically inhibiting Pim-2 kinase activity or by genetically knocking out Pim-2 in rodent Treg cells. Deficiency of Pim-2 activity increases murine host resistance to dextran sodium sulfate-induced colitis in vivo, and a Pim-2 small molecule kinase inhibitor also modified Treg cell functions. Our studies define a pathway for limiting the regulation of Foxp3 function because the Pim-2 kinase represents a potential therapeutic target for modulating the Treg cell suppressive activities in controlling immune responses.