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J Immunol. 2017 Jun 1;198(11):4244-4254. doi: 10.4049/jimmunol.1601912. Epub 2017 May 3.

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

Author information

1
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294; and.
2
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294.
3
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294; and hqin@uab.edu tika@uab.edu.

Abstract

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-γ-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-γ+ 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.

PMID:
28468969
PMCID:
PMC5512439
DOI:
10.4049/jimmunol.1601912
[Indexed for MEDLINE]
Free PMC Article

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