CD5 enhances Th17‐cell differentiation by regulating IFN‐γ response and RORγt localization

• Published in: European journal of immunology 2014-04, Vol.44 (4), p.1137-1142
• Main Authors: McGuire, Donald J., Rowse, Amber L., Li, Hao, Peng, Binghao J., Sestero, Christine M., Cashman, Kevin S., De Sarno, Patrizia, Raman, Chander
• Format: Article
• Language: English
• Subjects: AKT; Animals; Casein Kinase II - genetics; Casein Kinase II - immunology; Casein Kinase II - metabolism; CD5; CD5 Antigens - genetics; CD5 Antigens - immunology; CD5 Antigens - metabolism; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Nucleus - immunology; Cell Nucleus - metabolism; Cells, Cultured; Cytokine receptor signaling; Flow Cytometry; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - immunology; Glycogen Synthase Kinase 3 - metabolism; Immunohistochemistry; Interferon gamma Receptor; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - immunology; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Receptors, Interferon - immunology; Receptors, Interferon - metabolism; Signal Transduction - genetics; Signal Transduction - immunology; Th17; Th17 Cells - immunology; Th17 Cells - metabolism
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201343998

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‐γ‐mediated inhibition. In the absence of CD5‐CK2 signaling, we observed decreased activity of S6K and attenuated nuclear translocation of RORγt (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‐γ axis in regulating Th‐cell differentiation and provide a possible means to dampen Th17‐type responses in autoimmune diseases.