Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 44, Issue 4, Pages 1137-1142Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.201343998
Keywords
AKT; CD5; Cytokine receptor signaling; Glycogen synthase kinase 3; Th17
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Funding
- National Institutes of Health (NIH) [T32-AI007051, R01 NS064261, AI1076562]
- National Multiple Sclerosis Society [RG3891]
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Mechanisms that modulate the generation of Th17 cells are incompletely understood. We report that the activation of casein kinase 2 (CK2) by CD5 is essential for the efficient generation of Th17 cells in vitro and in vivo. In our study, the CD5-CK2 signaling pathway enhanced TCR-induced activation of AKT and promoted the differentiation of Th17 cells by two independent mechanisms: inhibition of glycogen synthase kinase 3 (GSK3) and activation of mTOR. Genetic ablation of the CD5-CK2 signaling pathway attenuated TCR-induced AKT activation and consequently increased activity of GSK3 in Th17 cells. This resulted in increased sensitivity of Th17 cells to IFN--mediated inhibition. In the absence of CD5-CK2 signaling, we observed decreased activity of S6K and attenuated nuclear translocation of RORt (ROR is retinoic acid receptor related orphan receptor). These results reveal a novel and essential function of the CD5-CK2 signaling pathway and GSK3-IFN- axis in regulating Th-cell differentiation and provide a possible means to dampen Th17-type responses in autoimmune diseases.
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