Abstract
Metabolic syndrome is characterized by disturbances in glucose homeostasis and the development of low-grade systemic inflammation, which increase the risk to develop type 2 diabetes mellitus (T2DM). Type-2 innate lymphoid cells (ILC2s) are a recently discovered immune population secreting Th2 cytokines. While previous studies show how ILC2s can play a critical role in the regulation of metabolic homeostasis in the adipose tissue, a therapeutic target capable of modulating ILC2 activation has yet to be identified. Here, we show that GITR, a member of the TNF superfamily, is expressed on both murine and human ILC2s. Strikingly, we demonstrate that GITR engagement of activated, but not naïve, ILC2s improves glucose homeostasis, resulting in both protection against insulin resistance onset and amelioration of established insulin- resistance. Together, these results highlight the critical role of GITR as a novel therapeutic molecule against T2DM and its fundamental role as an immune checkpoint for activated ILC2s.
Highlights
Metabolic syndrome is characterized by disturbances in glucose homeostasis and the development of low-grade systemic inflammation, which increase the risk to develop type 2 diabetes mellitus (T2DM)
Based on our recent observations that ICOS, a costimulatory molecule expressed by immune cells, was expressed by ILC2s and modulated their effector function and homeostasis[13], we first assessed whether Glucocorticoid-induced tumor necrosis factor receptor (GITR) was expressed on naïve and IL-33-activated ILC2s
We discovered that GITR engagement on ILC2s with the specific agonist DTA-1 induces Th2 cytokine secretion in activated ILC2s but has no effect on naïve ILC2s
Summary
Metabolic syndrome is characterized by disturbances in glucose homeostasis and the development of low-grade systemic inflammation, which increase the risk to develop type 2 diabetes mellitus (T2DM). We demonstrate that GITR engagement of activated, but not naïve, ILC2s improves glucose homeostasis, resulting in both protection against insulin resistance onset and amelioration of established insulin- resistance Together, these results highlight the critical role of GITR as a novel therapeutic molecule against T2DM and its fundamental role as an immune checkpoint for activated ILC2s. GITR is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule[17,18] It is upregulated in the context of inflammation and acts as an important costimulatory signal in T lymphocyte subpopulations, as studies have shown that engagement of GITR with its ligand (GITRL) in vivo induces T cell expansion and cytokine production[19,20,21,22,23]. Our findings provide new insights on GITR’s role in ILC2s and introduce GITR engagement as an ideal therapeutic target against T2DM
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