c-Abl-Mediated Tyrosine Phosphorylation of the T-bet DNA-Binding Domain Regulates CD4+ T-Cell Differentiation and Allergic Lung Inflammation
c-Abl-Mediated Tyrosine Phosphorylation of the T-bet DNA-Binding Domain Regulates CD4+ T-Cell Differentiation and Allergic Lung Inflammation
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DOI：
10.1128/mcb.05383-11
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发表时间：
2011-08-01
影响因子：
5.3
通讯作者：
Fang, Deyu
中科院分区：
文献类型：
--
作者：
Chen, An;Lee, Sang-Myeong;Fang, Deyu
酪氨酸激酶c-Abl是T细胞完全活化所必需的，而其在T细胞分化中的作用尚未被表征。我们报道了c-Abl缺陷使CD 4（+）T细胞向2型辅助性T细胞（Th 2）分化，并且c-Abl（-/-）小鼠更容易发生过敏性肺部炎症。c-Abl与Th 1谱系转录因子T-bet相互作用并使其磷酸化。c-Abl介导的磷酸化增强T-bet的转录激活。有趣的是，T-bet DNA结合域中的三个酪氨酸残基是c-Abl磷酸化的主要位点，这些酪氨酸残基的突变抑制了T-bet启动子DNA结合活性。c-Abl以T-bet依赖性方式调节Th细胞分化，因为CD 4（+）T细胞中T-bet的遗传缺失消除了c-Abl缺陷介导的Th 2分化增强。用野生型T-bet而不是其酪氨酸突变体重新引入T-bet无效的CD 4（+）T细胞，拯救γ干扰素（IFN-γ）的产生并抑制Th 2细胞因子的产生。因此，c-Abl催化T-bet的DNA结合结构域的酪氨酸磷酸化以调节CD 4（+）T细胞分化。
The tyrosine kinase c-Abl is required for full activation of T cells, while its role in T-cell differentiation has not been characterized. We report that c-Abl deficiency skews CD4(+) T cells to type 2 helper T cell (Th2) differentiation, and c-Abl(-/-)mice are more susceptible to allergic lung inflammation. c-Abl interacts with and phosphorylates T-bet, a Th1 lineage transcription factor. c-Abl-mediated phosphorylation enhances the transcriptional activation of T-bet. Interestingly, three tyrosine residues within the T-bet DNA-binding domain are the predominant sites of phosphorylation by c-Abl. Mutation of these tyrosine residues inhibits the promoter DNA-binding activity of T-bet. c-Abl regulates Th cell differentiation in a T-bet-dependent manner because genetic deletion of T-bet in CD4(+) T cells abolishes c-Abl-deficiency-mediated enhancement of Th2 differentiation. Reintroduction of T-bet-null CD4(+) T cells with wild-type T-bet, but not its tyrosine mutant, rescues gamma interferon (IFN-gamma) production and inhibits Th2 cytokine production. Therefore, c-Abl catalyzes tyrosine phosphorylation of the DNA-binding domain of T-bet to regulate CD4(+) T cell differentiation.