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J Immunol. 2018 Jul 15;201(2):383-392. doi: 10.4049/jimmunol.1701592. Epub 2018 Jun 11.

CK2 Controls Th17 and Regulatory T Cell Differentiation Through Inhibition of FoxO1.

Author information

1
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294.
2
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294 hqin@uab.edu tika@uab.edu.

Abstract

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.

PMID:
29891553
PMCID:
PMC6040220
[Available on 2019-07-15]
DOI:
10.4049/jimmunol.1701592

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