Function of protein kinase CK2 in CD4+ T cell polarization and EAE

Abstract

Abstract Auto-reactive CD4+ T cells drive many autoimmune diseases including multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). CK2 is a constitutively expressed and highly conserved serine/threonine kinase that promotes a number of pro-survival and pro-inflammatory signaling pathways including PI3K/Akt/mTOR, NF-kB 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 protein levels of the major catalytic subunit of CK2, CK2α, are induced in murine CD4+ T cells upon activation, correlating with an increase in overall kinase activity. In addition, CK2α expression is elevated in CD4+ T cells that are activated and infiltrate the CNS during experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Targeting the activity of CK2α using the small molecule inhibitor CX-4945 in vitro significantly inhibited Th17 cell polarization and promoted FOXP3 expression in both Th17 and Treg polarizing conditions with no appreciable effect on the generation of Th1 cells. In vivo treatment with CX-4945 during EAE resulted in a dampened Th17 response in the periphery and a decrease in IL-17A+ and IL-17A+IFN-γ+ CD4+ T cells present in the spinal cord. Continued CX-4945 treatment significantly reduced the severity of EAE clinical symptoms and increased the percentage of FOXP3+ Tregs in the spinal cord during disease resolution. Our data implicate CK2 as a novel regulator of the Th17/Treg cell axis, and suggest that CK2 could be targeted for the treatment of CD4+ T cell-driven autoimmune disorders.