The Receptor SIGIRR Suppresses Th17 Cell Proliferation via Inhibition of the Interleukin-1 Receptor Pathway and mTOR Kinase Activation
Copyright policy )The Receptor SIGIRR Suppresses Th17 Cell Proliferation via Inhibition of the Interleukin-1 Receptor Pathway and mTOR Kinase Activation
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.
- Cleveland Clinic United States
- University System of Ohio United States
- Johns Hopkins University School of Medicine
- Johns Hopkins Medicine United States
- Schering-Plough United States
Encephalomyelitis, Autoimmune, Experimental, Immunology, Immunoblotting, Enzyme-Linked Immunosorbent Assay, Cell Separation, Protein Serine-Threonine Kinases, Mice, T-Lymphocyte Subsets, Immunology and Allergy, Animals, Immunoprecipitation, Cell Lineage, MOLIMMUNO, Cell Proliferation, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Interleukin-17, Intracellular Signaling Peptides and Proteins, Receptors, Interleukin-1, Cell Differentiation, Flow Cytometry, Enzyme Activation, Infectious Diseases, CELLIMMUNO, Signal Transduction
Encephalomyelitis, Autoimmune, Experimental, Immunology, Immunoblotting, Enzyme-Linked Immunosorbent Assay, Cell Separation, Protein Serine-Threonine Kinases, Mice, T-Lymphocyte Subsets, Immunology and Allergy, Animals, Immunoprecipitation, Cell Lineage, MOLIMMUNO, Cell Proliferation, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Interleukin-17, Intracellular Signaling Peptides and Proteins, Receptors, Interleukin-1, Cell Differentiation, Flow Cytometry, Enzyme Activation, Infectious Diseases, CELLIMMUNO, Signal Transduction
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