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

Eur J Immunol. 2014 Apr;44(4):1137-42. doi: 10.1002/eji.201343998. Epub 2014 Jan 16.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD5 Antigens / genetics
  • CD5 Antigens / immunology*
  • CD5 Antigens / metabolism
  • Casein Kinase II / genetics
  • Casein Kinase II / immunology
  • Casein Kinase II / metabolism
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cell Nucleus / immunology
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Flow Cytometry
  • 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 Cells / immunology*
  • Th17 Cells / metabolism

Substances

  • CD5 Antigens
  • Cd5 protein, mouse
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Antigen, T-Cell
  • Receptors, Interferon
  • Interferon-gamma
  • Casein Kinase II
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3