Protein kinase CK2 governs the molecular decision between encephalitogenic T _H 17 cell and T _reg cell development

Abstract

T helper 17 (TH17) cells represent a discrete TH cell subset instrumental in the immune response to extracellular bacteria and fungi. However, TH17 cells are considered to be detrimentally involved in autoimmune diseases like multiple sclerosis (MS). In contrast to TH17 cells, regulatory T (Treg) cells were shown to be pivotal in the maintenance of peripheral tolerance. Thus, the balance between Treg cells and TH17 cells determines the severity of a TH17 cell-driven disease and therefore is a promising target for treating autoimmune diseases. However, the molecular mechanisms controlling this balance are still unclear. Here, we report that pharmacological inhibition as well as genetic ablation of the protein kinase CK2 (CK2) ameliorates experimental autoimmune encephalomyelitis (EAE) severity and relapse incidence. Furthermore, CK2 inhibition or genetic ablation prevents TH17 cell development and promotes the generation of Treg cells. Molecularly, inhibition of CK2 leads to reduced STAT3 phosphorylation and strongly attenuated expression of the IL-23 receptor, IL-17, and GM-CSF. Thus, these results identify CK2 as a nodal point in TH17 cell development and suggest this kinase as a potential therapeutic target to treat TH17 cell-driven autoimmune responses.

Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation

“…As this manuscript was in preparation, Ulges and colleagues (47) reported a protective effect of CX-4945 in vivo in EAE, which was also associated with an inhibition of Th17 cells and generation of Tregs. Thus our findings confirm that CK2 is critical in the control of the Th17/Treg axis during EAE.…”

“…Utilizing a genetic approach, we further demonstrate that knock-down of the major catalytic subunit, CK2α, in CD4 + T cells inhibits Th17 cell differentiation while promoting Tregs. Ulges and colleagues, however, demonstrated that ablation of CK2β in CD4 + T cells was sufficient to target the Th17/Treg axis (47). These results collectively implicate the involvement of both subunits in regulating the differentiation and function of CD4 + T cells.…”

Regulation of Th17 Differentiation by IKKα-Dependent and -Independent Phosphorylation of RORγt

“…It is possible that there is residual IKKα activity due to incomplete knockdown. There is another possibility that S376 can also be phosphorylated by other kinases including IRAK4, PKC-θ, and protein kinase CK2 that are reported to regulate Th17 differentiation (7, 44, 45). Our data do not support that S484 is phosphorylated in an IKKα dependent manner, and it thus remains unknown about the kinases responsible for phosphorylation of S484.…”

The multiple faces of CD5

“…In this context, pharmacological inhibition, or genetic silencing of CK2 in CD4 T cells leads to increased Treg generation and decreased Th17 differentiation, possibly as a result of lower STAT3 phosphorylation and the inhibition of the PI3K/AKT/mTOR pathways (Fig. ) . As CK2 is constitutively associated with CD5, the role of CD5 in T cell differentiation has been recently addressed.…”