Abstract
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.
Keywords:
AKT; CD5; Cytokine receptor signaling; Glycogen synthase kinase 3; Th17.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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CD5 Antigens / genetics
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CD5 Antigens / immunology*
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CD5 Antigens / metabolism
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Casein Kinase II / genetics
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Casein Kinase II / immunology
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Casein Kinase II / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cell Nucleus / immunology
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Cell Nucleus / metabolism
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Cells, Cultured
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Flow Cytometry
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Glycogen Synthase Kinase 3 / immunology
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Glycogen Synthase Kinase 3 / metabolism
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Immunohistochemistry
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Interferon gamma Receptor
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Interferon-gamma / immunology*
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Interferon-gamma / metabolism
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Interferon-gamma / pharmacology
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology*
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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Receptors, Interferon / immunology
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Receptors, Interferon / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology
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Th17 Cells / immunology*
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Th17 Cells / metabolism
Substances
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CD5 Antigens
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Cd5 protein, mouse
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Receptors, Antigen, T-Cell
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Receptors, Interferon
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Interferon-gamma
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Casein Kinase II
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3