title: The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation.
abstract: Interleukin-1 (IL-1)-mediated signaling in T cells is essential for T helper 17 (Th17) cell differentiation. We showed here that SIGIRR, a negative regulator of IL-1 receptor and Toll-like receptor signaling, was induced during Th17 cell lineage commitment and governed Th17 cell differentiation and expansion through its inhibitory effects on IL-1 signaling. The absence of SIGIRR in T cells resulted in increased Th17 cell polarization in vivo upon myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide immunization. Recombinant IL-1 promoted a marked increase in the proliferation of SIGIRR-deficient T cells under an in vitro Th17 cell-polarization condition. Importantly, we detected increased IL-1-induced phosphorylation of JNK and mTOR kinase in SIGIRR-deficient Th17 cells compared to wild-type Th17 cells. IL-1-induced proliferation was abolished in mTOR-deficient Th17 cells, indicating the essential role of mTOR activation. Our results demonstrate an important mechanism by which SIGIRR controls Th17 cell expansion and effector function through the IL-1-induced mTOR signaling pathway.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Muhammet F
authors.initials: MF
authors.lastname: Gulen
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Kang
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bulek
authors.forename: Wan
authors.initials: W
authors.lastname: Youzhong
authors.forename: Tae Whan
authors.initials: TW
authors.lastname: Kim
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Cengiz Z
authors.initials: CZ
authors.lastname: Altuntas
authors.forename: Kristian
authors.initials: K
authors.lastname: Sass Bak-Jensen
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: McGeachy
authors.forename: Jeong-Su
authors.initials: JS
authors.lastname: Do
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Greg M
authors.initials: GM
authors.lastname: Delgoffe
authors.forename: Booki
authors.initials: B
authors.lastname: Min
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
authors.forename: Vincent K
authors.initials: VK
authors.lastname: Tuohy
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cua
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation; D002469:Cell Separation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015151:Immunoblotting; D047468:Immunoprecipitation; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014162:Transfection
chemical_list: D020381:Interleukin-17; D047908:Intracellular Signaling Peptides and Proteins; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases