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.

Reduced Fragmentation of IGFBP-2 and IGFBP-3 as a Potential Mechanism for Decreased Ratio of IGF-II to IGFBPs in Cerebrospinal Fluid in Response to Repeated Intrathecal Administration of Triamcinolone Acetonide in Patients With Multiple Sclerosis

“…IGF-I is required for brain growth and development, and the lack of IGF-I in knockout mice resulted in reduced brain growth and hypomyelination (6). In addition, IGF-I, as an effector of Th17/ Treg cell balance, induced proinflammatory responses in EAE (13). Therefore, IGF-I is not only considered as a neuroprotective agent but is also discussed concerning health-related fitness in MS patients after aerobic training (19).…”

“…A very recent publication has demonstrated that, in fact, IGFs exert proinflammatory responses in EAE. This effect was shown to be dependent on the presence of IGF-I receptor and mediated via the Akt signaling pathway (13). At the cellular level, IGF-I induced the differentiation of T helper 17 (Th17) cells and therefore impacted the Th17 and regulatory T cell (Treg) balance (13), which is required for host defense and adequate immune tolerance.…”

“…This effect was shown to be dependent on the presence of IGF-I receptor and mediated via the Akt signaling pathway (13). At the cellular level, IGF-I induced the differentiation of T helper 17 (Th17) cells and therefore impacted the Th17 and regulatory T cell (Treg) balance (13), which is required for host defense and adequate immune tolerance. Notably, the Treg-Th17 balance is altered under conditions of autoimmune diseases, including MS (14,15).…”

Co-Occurrence of ANCA-Associated Vasculitis and Sjögren’s Syndrome in a Patient With Acromegaly: A Case Report and Retrospective Single-Center Review of Acromegaly Patients

“…A mouse study recently provided evidence for IGF-1-mediated Th17/Treg dysbalance, favoring development of autoimmunity. Mice without the IGF-1 receptor on T cells showed a substantially reduced disease severity in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis ( 22 , 23 ). Interestingly, high IGF-1 was demonstrated in labial glands of pSS patients ( 24 ).…”

MAIT Cells in Barrier Tissues: Lessons from Immediate Neighbors

“…Growth factors also regulate tissues and could influence MAIT cells. One example is insulin-like growth factor 1 (IGF-1) signaling, which promotes STAT3 signaling and aerobic glycolysis to increase type-17 effector functionality of T H 17 and ILC3 (229). IGFbp4, an important modulator of IGF1 signaling, is enriched in murine RORgt + T H 17, T reg , and ILC3.…”