Laboratory of Molecular Biology and Immunology, National Institutes of Health, Baltimore, Maryland, USA.
FASEB J. 2011 Oct;25(10):3634-45. doi: 10.1096/fj.11-186924. Epub 2011 Jun 17.
Krüppel-like factor 4 (KLF4), a transcription factor, plays a key role in the pluripotency of stem cells. We sought to determine the function of KLF4 in T-cell development and differentiation by using T-cell-specific Klf4-knockout (KO) mice. We found that KLF4 was highly expressed in thymocytes and mature T cells and was rapidly down-regulated in mature T cells after activation. In Klf4-KO mice, we observed a modest reduction of thymocytes (27%) due to the reduced proliferation of double-negative (DN) thymocytes. We demonstrated that a direct repression of Cdkn1b by KLF4 was a cause of decreased DN proliferation. During in vitro T-cell differentiation, we observed significant reduction of IL-17-expressing CD4(+) T cells (Th17; 24%) but not in other types of Th differentiation. The reduction of Th17 cells resulted in a significant attenuation of the severity (35%) of experimental autoimmune encephalomyelitis in vivo in Klf4-KO mice as compared with the Klf4 wild-type littermates. Finally, we demonstrated that KLF4 directly binds to the promoter of Il17a and positively regulates its expression. In summary, these findings identify KLF4 as a critical regulator in T-cell development and Th17 differentiation.
Krüppel 样因子 4（KLF4）是一种转录因子，在干细胞的多能性中发挥关键作用。我们试图通过使用 T 细胞特异性 Klf4 敲除（KO）小鼠来确定 KLF4 在 T 细胞发育和分化中的功能。我们发现 KLF4 在胸腺细胞和成熟 T 细胞中高度表达，并在成熟 T 细胞活化后迅速下调。在 Klf4-KO 小鼠中，我们观察到由于双阴性（DN）胸腺细胞增殖减少，胸腺细胞减少了 27%。我们证明，KLF4 对 Cdkn1b 的直接抑制是 DN 增殖减少的原因。在体外 T 细胞分化过程中，我们观察到表达 IL-17 的 CD4(+) T 细胞（Th17；24%）的显著减少，但其他类型的 Th 分化没有减少。Th17 细胞的减少导致 Klf4-KO 小鼠体内实验性自身免疫性脑脊髓炎的严重程度（35%）显著降低，与 Klf4 野生型同窝小鼠相比。最后，我们证明 KLF4 直接结合到 Il17a 的启动子上，并正向调节其表达。总之，这些发现确定 KLF4 是 T 细胞发育和 Th17 分化的关键调节因子。
