Insulin-Like Growth Factors Are Key Regulators of T Helper 17 Regulatory T Cell Balance in Autoimmunity

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, w...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2020-04, Vol.52 (4), p.650-667.e10
Main Authors: DiToro, Daniel, Harbour, Stacey N., Bando, Jennifer K., Benavides, Gloria, Witte, Steven, Laufer, Vincent A., Moseley, Carson, Singer, Jeffery R., Frey, Blake, Turner, Henrietta, Bruning, Jens, Darley-Usmar, Victor, Gao, Min, Conover, Cheryl, Hatton, Robin D., Frank, Stuart, Colonna, Marco, Weaver, Casey T.
Format: Article
Language:English
Subjects:
AKT protein
Animals
Antigens
Apoptosis
Autoimmunity
CD4 T cell
Cell Communication
Cell cycle
Cell Differentiation
Cell Lineage - genetics
Cell Lineage - immunology
Differentiation (biology)
EAE
Encephalomyelitis, Autoimmune, Experimental - chemically induced
Encephalomyelitis, Autoimmune, Experimental - genetics
Encephalomyelitis, Autoimmune, Experimental - immunology
Encephalomyelitis, Autoimmune, Experimental - pathology
Experimental allergic encephalomyelitis
Female
Gene expression
Gene Expression Regulation
Glycolysis
Growth factors
Helper cells
IGF1R
Immune Tolerance
Immunity, Innate
Immunological tolerance
Inflammation
Insulin
insulin-like growth factor
Insulin-like growth factors
Kinases
Ligands
Lymphocyte Activation
Lymphocytes
Lymphocytes T
Lymphoid cells
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Multiple sclerosis
Myelin-Oligodendrocyte Glycoprotein - administration & dosage
Pathogenesis
Peptide Fragments - administration & dosage
Physiology
Proteins
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - immunology
Rapamycin
Receptor, IGF Type 1 - genetics
Receptor, IGF Type 1 - immunology
Signal Transduction
Signaling
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - pathology
Th17
Th17 Cells - immunology
Th17 Cells - pathology
TOR protein
TOR Serine-Threonine Kinases - genetics
TOR Serine-Threonine Kinases - immunology
Transcription factors
Treg
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Summary: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. •IGFs favor Th17 cell differentiation over that of Treg cells•IGF1R augments AKT-mTOR and STAT3 signaling and increases aerobic glycolysis•Signaling through IGF1R increases Th17 numbers and pathogenicity in EAE•ILC3 cell function is similarly affected by insulin-like growth factors The IGF system is a well-known regulator of cell growth, differentiation, metabolism, and function. DiToro and colleagues demonstrate that insulin-like growth factors support inflammatory responses by modulating these processes in Th17 and Treg cells, and in ILC3s.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2020.03.013