title: CD5 enhances Th17-cell differentiation by regulating IFN-γ response and RORγt localization.
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.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: McGuire
authors.forename: Amber L
authors.initials: AL
authors.lastname: Rowse
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Binghao J
authors.initials: BJ
authors.lastname: Peng
authors.forename: Christine M
authors.initials: CM
authors.lastname: Sestero
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Cashman
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Sarno
authors.forename: Chander
authors.initials: C
authors.lastname: Raman
mesh_terms: D000818:Animals; D018956:CD5 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D047390:Casein Kinase II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017471:Receptors, Interferon / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D018956:CD5 Antigens; D047390:Casein Kinase II; D038362:Glycogen Synthase Kinase 3; D007371:Interferon-gamma; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C526836:Cd5 protein, mouse
keywords: AKT; CD5; Cytokine receptor signaling; Glycogen synthase kinase 3; Th17