Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294.
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294
J Immunol. 2018 Jul 15;201(2):383-392. doi: 10.4049/jimmunol.1701592. Epub 2018 Jun 11.
Growing evidence demonstrates that the highly conserved serine/threonine kinase CK2 promotes Th17 cell differentiation while suppressing the generation of Foxp3 regulatory T cells (Tregs); however, the exact mechanism by which CK2 regulates the Th17/Treg axis remains unclear. CK2 can be composed of three distinct subunits: two catalytic subunits, CK2α and CK2α', and the regulatory subunit CK2β. We generated mice that lack the major catalytic subunit of CK2, CK2α, specifically in mature T cells using the distal Lck-Cre (CK2α). Importantly, CK2α deficiency resulted in a significant decrease in the overall kinase activity of CK2. Further, CK2α deficiency resulted in a significant defect in Th17 cell polarization and a reciprocal increase in Tregs both in vitro and in vivo in the context of autoimmune neuroinflammation. The transcription factor forkhead box protein O1 (FoxO1) directly inhibits Th17 cell differentiation and is essential for the generation of Tregs. CK2α CD4 T cells exhibit less phosphorylated FoxO1 and a corresponding increase in the transcription of FoxO1-regulated genes. Treatment of CK2α CD4 T cells with the FoxO1 inhibitor AS1842856 or short hairpin RNA knockdown of FoxO1 is sufficient to rescue Th17 cell polarization. Through use of a genetic approach to target CK2 kinase activity, the current study provides evidence of a major mechanism by which CK2 regulates the Th17/Treg axis through the inhibition of FoxO1.
越来越多的证据表明，高度保守的丝氨酸/苏氨酸激酶 CK2 促进 Th17 细胞分化，同时抑制 Foxp3 调节性 T 细胞（Treg）的产生；然而，CK2 调节 Th17/Treg 轴的确切机制仍不清楚。CK2 可以由三个不同的亚基组成：两个催化亚基 CK2α 和 CK2α'，以及调节亚基 CK2β。我们使用远侧 Lck-Cre（CK2α）在成熟 T 细胞中特异性缺失 CK2 的主要催化亚基 CK2α 生成了小鼠。重要的是，CK2α 缺失导致 CK2 的整体激酶活性显著降低。此外，CK2α 缺失导致 Th17 细胞极化明显缺陷，自身免疫性神经炎症情况下体外和体内的 Treg 均显著增加。叉头框蛋白 O1（FoxO1）转录因子直接抑制 Th17 细胞分化，是产生 Treg 的必要条件。CK2α CD4 T 细胞表现出较少的磷酸化 FoxO1 和 FoxO1 调节基因的转录相应增加。用 FoxO1 抑制剂 AS1842856 或 FoxO1 的短发夹 RNA 敲低处理 CK2α CD4 T 细胞足以挽救 Th17 细胞极化。通过使用靶向 CK2 激酶活性的遗传方法，本研究提供了证据表明，CK2 通过抑制 FoxO1 来调节 Th17/Treg 轴的主要机制。
