Abstract
Appropriate balance of T helper 17 (Th17) and regulatory T (Treg) cells maintains immune tolerance and host defense. Disruption of Th17-Treg cell balance is implicated in a number of immune-mediated diseases, many of which display dysregulation of the insulin-like growth factor (IGF) system. Here, we show that, among effector T cell subsets, Th17 and Treg cells selectively expressed multiple components of the IGF system. Signaling through IGF receptor (IGF1R) activated the protein kinase B-mammalian target of rapamycin (AKT-mTOR) pathway, increased aerobic glycolysis, favored Th17 cell differentiation over that of Treg cells, and promoted a heightened pro-inflammatory gene expression signature. Group 3 innate lymphoid cells (ILC3s), but not ILC1s or ILC2s, were similarly responsive to IGF signaling. Mice with deficiency of IGF1R targeted to T cells failed to fully develop disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Thus, the IGF system represents a previously unappreciated pathway by which type 3 immunity is modulated and immune-mediated pathogenesis controlled.
Keywords:
CD4 T cell; EAE; IGF1R; Th17; Treg; insulin-like growth factor; multiple sclerosis.
Copyright © 2020 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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Autoimmunity*
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Cell Communication
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Cell Differentiation
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Cell Lineage / genetics
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Cell Lineage / immunology
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Encephalomyelitis, Autoimmune, Experimental / chemically induced
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Female
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Gene Expression Regulation
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Immune Tolerance
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Immunity, Innate
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Lymphocyte Activation
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Myelin-Oligodendrocyte Glycoprotein / administration & dosage
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Peptide Fragments / administration & dosage
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology*
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / immunology*
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Signal Transduction
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / pathology
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / immunology*
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Th17 Cells / immunology*
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Th17 Cells / pathology
Substances
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Igf1r protein, mouse
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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myelin oligodendrocyte glycoprotein (35-55)
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mTOR protein, mouse
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Receptor, IGF Type 1
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases