@article{9f69917d69424244a5df6f5ef8d2ed8e,
title = "Insulin-Like Growth Factors Are Key Regulators of T Helper 17 Regulatory T Cell Balance in Autoimmunity",
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",
author = "Daniel DiToro and Harbour, {Stacey N.} and Bando, {Jennifer K.} and Gloria Benavides and Steven Witte and Laufer, {Vincent A.} and Carson Moseley and Singer, {Jeffery R.} and Blake Frey and Henrietta Turner and Jens Bruning and Victor Darley-Usmar and Min Gao and Cheryl Conover and Hatton, {Robin D.} and Stuart Frank and Marco Colonna and Weaver, {Casey T.}",
note = "Funding Information: The authors thank Drs. Etty Beneveniste, Laurie Harrington, Lou Justement, and Robin Lorenz (University of Alabama Birmingham [UAB]), and members of the Weaver laboratory for their helpful comments and suggestions. We gratefully acknowledge Jeremy Day (La Jolla Institute of Allergy and Immunology) for assistance with gene expression studies. We also thank Jon Wright, Brenda Dale, and Alanna Smith for expert technical assistance, Connie Rutledge for editorial assistance, and the UAB Center for AIDS Research Flow Cytometry Core and UAB Epitope Recognition and Immunoreagent Core Facility flow cytometric sorting and antibody preparations, respectively. This work was supported by an NIH training grant T32 AI007051 to D.D.; NIH K99 DK118110 to J.K.B.; NIH R01 grants to C.H.C. S.J.F. R.D.H. and C.T.W.; and UAB Institutional Funds to C.T.W. D.D. and C.T.W. designed the research strategy and wrote the manuscript. D.D. S.N.H. J.K.B. G.B. C.M. and H.T. performed or assisted with experiments. D.D. S.N.H. J.K.B. G.B. S.W. V.L. M.G. C.M. R.D.H. V.D.U. M.C. and C.T.W. analyzed data. J.B. C.H.C. and S.J.F. provided key reagents and critical expertise. The authors declare no competing interests. Funding Information: The authors thank Drs. Etty Beneveniste, Laurie Harrington, Lou Justement, and Robin Lorenz (University of Alabama Birmingham [UAB]), and members of the Weaver laboratory for their helpful comments and suggestions. We gratefully acknowledge Jeremy Day (La Jolla Institute of Allergy and Immunology) for assistance with gene expression studies. We also thank Jon Wright, Brenda Dale, and Alanna Smith for expert technical assistance, Connie Rutledge for editorial assistance, and the UAB Center for AIDS Research Flow Cytometry Core and UAB Epitope Recognition and Immunoreagent Core Facility flow cytometric sorting and antibody preparations, respectively. This work was supported by an NIH training grant T32 AI007051 to D.D.; NIH K99 DK118110 to J.K.B.; NIH R01 grants to C.H.C., S.J.F., R.D.H., and C.T.W.; and UAB Institutional Funds to C.T.W. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = apr,
day = "14",
doi = "10.1016/j.immuni.2020.03.013",
language = "English (US)",
volume = "52",
pages = "650--667.e10",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "4",
}