Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Mol Cell Biol. 2011 Aug;31(16):3445-56. doi: 10.1128/MCB.05383-11. Epub 2011 Jun 20.
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-γ) 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.
酪氨酸激酶 c-Abl 是 T 细胞完全激活所必需的，但其在 T 细胞分化中的作用尚未确定。我们报告称，c-Abl 缺陷使 CD4(+)T 细胞向辅助性 T 细胞 2 型（Th2）分化倾斜，而 c-Abl(-/-) 小鼠更容易发生过敏性肺炎症。c-Abl 与 Th1 谱系转录因子 T-bet 相互作用并使其磷酸化。c-Abl 介导的磷酸化增强了 T-bet 的转录激活。有趣的是，T-bet DNA 结合域内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 的启动子 DNA 结合活性。c-Abl 通过 T-bet 依赖的方式调节 Th 细胞分化，因为在 CD4(+)T 细胞中缺失 T-bet 可消除 c-Abl 缺陷介导的 Th2 分化增强。用野生型 T-bet 而非其酪氨酸突变体重新引入 T-bet 缺失的 CD4(+)T 细胞可恢复 γ干扰素（IFN-γ）的产生并抑制 Th2 细胞因子的产生。因此，c-Abl 催化 T-bet DNA 结合域的酪氨酸磷酸化，从而调节 CD4(+)T 细胞分化。
