Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
Division of Immunology and Neurology, Mayo Clinic, Rochester, Minnesota; and.
Am J Physiol Cell Physiol. 2015 Mar 1;308(5):C362-71. doi: 10.1152/ajpcell.00262.2014. Epub 2014 Dec 3.
KLF10 has recently elicited significant attention as a transcriptional regulator of transforming growth factor-β1 (TGF-β1) signaling in CD4(+) T cells. In the current study, we demonstrate a novel role for KLF10 in the regulation of TGF-β receptor II (TGF-βRII) expression with functional relevance in antiviral immune response. Specifically, we show that KLF10-deficient mice have an increased number of effector/memory CD8(+) T cells, display higher levels of the T helper type 1 cell-associated transcription factor T-bet, and produce more IFN-γ following in vitro stimulation. In addition, KLF10(-/-) CD8(+) T cells show enhanced proliferation in vitro and homeostatic proliferation in vivo. Freshly isolated CD8(+) T cells from the spleen of adult mice express lower levels of surface TGF-βRII (TβRII). Congruently, in vitro activation of KLF10-deficient CD8(+) T cells upregulate TGF-βRII to a lesser extent compared with wild-type (WT) CD8(+) T cells, which results in attenuated Smad2 phosphorylation following TGF-β1 stimulation compared with WT CD8(+) T cells. Moreover, we demonstrate that KLF10 directly binds to the TGF-βRII promoter in T cells, leading to enhanced gene expression. In vivo viral infection with Daniel's strain Theiler's murine encephalomyelitis virus (TMEV) also led to lower expression of TGF-βRII among viral-specific KLF10(-/-) CD8(+) T cells and a higher percentage of IFN-γ-producing CD8(+) T cells in the spleen. Collectively, our data reveal a critical role for KLF10 in the transcriptional activation of TGF-βRII in CD8(+) T cells. Thus, KLF10 regulation of TGF-βRII in this cell subset may likely play a critical role in viral and tumor immune responses for which the integrity of the TGF-β1/TGF-βRII signaling pathway is crucial.
KLF10 最近作为转化生长因子-β1（TGF-β1）信号在 CD4(+)T 细胞中转录调节因子引起了广泛关注。在本研究中，我们证明了 KLF10 在调节 TGF-β 受体 II（TGF-βRII）表达中的新作用，这在抗病毒免疫反应中具有功能相关性。具体来说，我们表明 KLF10 缺陷小鼠具有更多的效应记忆 CD8(+)T 细胞，显示出更高水平的 T 辅助细胞 1 型相关转录因子 T-bet，并在体外刺激后产生更多的 IFN-γ。此外，KLF10(-/-)CD8(+)T 细胞在体外表现出更强的增殖能力，体内稳态增殖能力增强。成年小鼠脾脏中新鲜分离的 CD8(+)T 细胞表面 TGF-βRII（TβRII）表达水平较低。一致地，与野生型（WT）CD8(+)T 细胞相比，体外激活 KLF10 缺陷型 CD8(+)T 细胞上调 TGF-βRII 的程度较小，这导致与 WT CD8(+)T 细胞相比，TGF-β1 刺激后 Smad2 磷酸化减弱。此外，我们证明 KLF10 直接结合 T 细胞中的 TGF-βRII 启动子，导致基因表达增强。体内感染 Daniel 株 Theiler's 鼠脑脊髓炎病毒（TMEV）也导致病毒特异性 KLF10(-/-)CD8(+)T 细胞中 TGF-βRII 表达降低，脾脏中 IFN-γ 产生 CD8(+)T 细胞的百分比升高。总之，我们的数据揭示了 KLF10 在 CD8(+)T 细胞中 TGF-βRII 的转录激活中的关键作用。因此，KLF10 对该细胞亚群中 TGF-βRII 的调节可能在病毒和肿瘤免疫反应中发挥关键作用，其中 TGF-β1/TGF-βRII 信号通路的完整性至关重要。
