Protein Kinase CK2 Controls the Fate Between Th17 Cell and Regulatory T Cell Differentiation CK2 Regulates the Th17/Treg Axis

• Published in: The Journal of immunology (1950) 2017-05, Vol.198 (11), p.4244-4254
• Main Authors: Gibson, Sara A, Yang, Wei, Yan, Zhaoqi, Liu, Yudong, Rowse, Amber L, Weinmann, Amy S., Qin, Hongwei, Benveniste, Etty N.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601912

CK2 is a highly conserved and pleiotropic serine/threonine kinase that promotes many pro-survival and pro-inflammatory signaling pathways including PI3K/Akt/mTOR and JAK/STAT. These pathways are essential for CD4 + T cell activation and polarization, but little is known about how CK2 functions in T cells. Here we demonstrate that CK2 expression and kinase activity are induced upon CD4 + T cell activation. Targeting the catalytic activity of CK2 using the next generation small molecule inhibitor CX-4945 in vitro significantly and specifically inhibited mouse and human Th17 cell differentiation while promoting the generation of Foxp3 + Tregs. These findings were associated with suppression of PI3K/Akt/mTOR activation and STAT3 phosphorylation upon CX-4945 treatment. Furthermore, we demonstrate that CX-4945 treatment inhibits the maturation of Th17 cells into inflammatory IFN-γ co-producing effector cells. The Th17/Treg cell axis and maturation of Th17 cells are major contributing factors to the pathogenesis of many autoimmune disorders, including multiple sclerosis (MS). Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we demonstrate that in vivo administration of CX-4945 targets Akt/mTOR signaling in CD4 + T cells and the Th17/Treg axis throughout disease. Importantly, CX-4945 treatment after disease initiation significantly reduced disease severity, which was associated with a significant decrease in the frequency of pathogenic IFN-γ + and GM-CSF + Th17 cells present in the CNS. Our data implicate CK2 as a regulator of the Th17/Treg cell axis and Th17 cell maturation, and suggest that CK2 could be targeted for the treatment of Th17 cell-driven autoimmune disorders.