CK2 Controls Th17 and Regulatory T Cell Differentiation Through Inhibition of FoxO1.
CK2 Controls Th17 and Regulatory T Cell Differentiation Through Inhibition of FoxO1.
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DOI：
10.4049/jimmunol.1701592
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发表时间：
2018-07-15
期刊：
影响因子：
--
通讯作者：
Benveniste EN
中科院分区：
文献类型：
--
作者：
Gibson SA;Yang W;Yan Z;Qin H;Benveniste EN
越来越多的证据表明，高度保守的丝氨酸/苏氨酸激酶CK 2促进Th 17细胞分化，同时抑制Foxp 3 + T细胞的产生;然而，CK 2调节Th 17/Treg轴的确切机制仍不清楚。CK 2可由3个不同的亚基组成：2个催化亚基，CK 2 α和CK 2 α′，以及调节亚基，CK 2 β。我们产生了缺乏CK 2的主要催化亚基CK 2 α的小鼠，特别是在利用远端Lck-Cre（CK 2 α−/−）的成熟T细胞中。重要的是，CK 2 α缺乏导致CK 2的总体激酶活性显著降低。此外，在自身免疫性神经炎症的背景下，CK 2 α缺乏导致Th 17细胞极化的显著缺陷和体外和体内Tcl 2的相互增加。转录因子FoxO 1直接抑制Th 17细胞分化，并且对于Tcl 3的产生是必需的。CK 2 α−/− CD 4 + T细胞表现出较少的磷酸化FoxO 1和FoxO 1调节基因转录的相应增加。用FoxO 1抑制剂AS 1842856或Foxo 1的shRNA敲低治疗CK 2 α−/− CD 4 + T细胞足以拯救Th 17细胞极化。通过利用遗传学方法靶向CK 2激酶活性，目前的研究提供了CK 2通过抑制FoxO 1调节Th 17/Treg轴的主要机制的证据。
Growing evidence demonstrates that the highly conserved serine/threonine kinase CK2 promotes Th17 cell differentiation while suppressing the generation of Foxp3+ Tregs; however, the exact mechanism by which CK2 regulates the Th17/Treg axis remains unclear. CK2 can be comprised of 3 distinct subunits: 2 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 utilizing 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 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 shRNA knockdown of Foxo1 is sufficient to rescue Th17 cell polarization. Through utilization 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.
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DOI：
10.4049/jimmunol.1402554
发表时间：
2015-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hawse WF;Sheehan RP;Miskov-Zivanov N;Menk AV;Kane LP;Faeder JR;Morel PA
通讯作者：
Morel PA
影响因子：
4.3
作者：
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通讯作者：
Rother, Karen
影响因子：
4
作者：
Huang, Haojie;Tindall, Donald J.
通讯作者：
Tindall, Donald J.
影响因子：
12.4
作者：
Di Maira, G;Salvi, M;Ruzzene, M
通讯作者：
Ruzzene, M
DOI：
10.3390/ph10010027
发表时间：
2017-03-05
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Nuñez de Villavicencio-Diaz T;Rabalski AJ;Litchfield DW
通讯作者：
Litchfield DW