| First Author | Gibson SA | Year | 2017 |
| Journal | J Immunol | Volume | 198 |
| Issue | 11 | Pages | 4244-4254 |
| PubMed ID | 28468969 | Mgi Jnum | J:247727 |
| Mgi Id | MGI:5926664 | Doi | 10.4049/jimmunol.1601912 |
| Citation | Gibson SA, et al. (2017) Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation. J Immunol 198(11):4244-4254 |
| abstractText | CK2 is a highly conserved and pleiotropic serine/threonine kinase that promotes many prosurvival and proinflammatory 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. In this article, 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+ regulatory T cells (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-gamma-coproducing effector cells. The Th17/Treg axis and maturation of Th17 cells are major contributing factors to the pathogenesis of many autoimmune disorders, including multiple sclerosis. Using a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis, 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-gamma+ and GM-CSF+ Th17 cells in the CNS. Our data implicate CK2 as a regulator of the Th17/Treg axis and Th17 cell maturation and suggest that CK2 could be targeted for the treatment of Th17 cell-driven autoimmune disorders. |
