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.
Copyright 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / immunology*
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Cell Lineage / immunology
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Cell Proliferation
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Cell Separation
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Enzyme Activation / immunology
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Immunoblotting
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Immunoprecipitation
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Interleukin-17 / immunology*
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Interleukin-17 / metabolism
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Intracellular Signaling Peptides and Proteins / immunology*
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Knockout
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Protein Serine-Threonine Kinases / immunology*
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Protein Serine-Threonine Kinases / metabolism
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Receptors, Interleukin-1 / immunology*
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Receptors, Interleukin-1 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / immunology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Helper-Inducer / cytology*
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / metabolism
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TOR Serine-Threonine Kinases
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Transfection
Substances
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Interleukin-17
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Intracellular Signaling Peptides and Proteins
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Receptors, Interleukin-1
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SIGIRR protein, mouse
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mTOR protein, mouse
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases