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

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, CK2 alpha and CK2 alpha', and the regulatory subunit CK2 beta. We generated mice that lack the major catalytic subunit of CK2, CK2 alpha, specifically in mature T cells using the distal Lck-Cre (CK2 alpha(-/-)). Importantly, CK2 alpha deficiency resulted in a significant decrease in the overall kinase activity of CK2. Further, CK2 alpha 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. CK2 alpha(-/-) CD4(+) T cells exhibit less phosphorylated FoxO1 and a corresponding increase in the transcription of FoxO1-regulated genes. Treatment of CK2 alpha(-/-) 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.