Type 2 Innate Lymphoid Cells: Protectors in Type 2 Diabetes

Abstract

Type 2 innate lymphoid cells (ILC2) are the innate counterparts of Th2 cells and are critically involved in the maintenance of homeostasis in a variety of tissues. Instead of expressing specific antigen receptors, ILC2s respond to external stimuli such as alarmins released from damage. These cells help control the delicate balance of inflammation in adipose tissue, which is a determinant of metabolic outcome. ILC2s play a key role in the pathogenesis of type 2 diabetes mellitus (T2DM) through their protective effects on tissue homeostasis. A variety of crosstalk takes place between resident adipose cells and ILC2s, with each interaction playing a key role in controlling this balance. ILC2 effector function is associated with increased browning of adipose tissue and an anti-inflammatory immune profile. Trafficking and maintenance of ILC2 populations are critical for tissue homeostasis. The metabolic environment and energy source significantly affect the number and function of ILC2s in addition to affecting their interactions with resident cell types. How ILC2s react to changes in the metabolic environment is a clear determinant of the severity of disease. Treating sources of metabolic instability via critical immune cells provides a clear avenue for modulation of systemic homeostasis and new treatments of T2DM.

Keywords: ILC2; immune regulation; immunometabolism; neuroimmunology; thermogenesis; type 2 diabetes.

Figure 1

Role of ILC2s in Protecting Adipose Homeostasis and Promoting Beige Adipocytes. ILC2s begin a cascade of anti-inflammatory effects on the adipose tissue which allow for the browning of adipose tissue. During browning, adipocytes increase mitochondrial output and browning genes. Peripheral nerves are protected by ILC2s and communicate through neuronal factors such release of neuropeptides. In homeostasis, the balance of inflammation is maintained via healthy response to peripheral signals. During metabolic disturbances, the cytokines IL-12 and IFN-γ polarize ILC progenitors to become ILC1s responsible for damage of adipose tissue and systemic dysfunction. During this process, M1 macrophages are recruited to the adipose tissue and catabolize catecholamines like NE leading to insulin resistance. Chronic release of TNF-α also contribute to poor responses to insulin and T2DM. DR3, death receptor 3; Eosin, eosinophil; GITR: Glucocorticoid-Induced TNFR-Related protein; ICOS, inducible T-cell co-stimulator; IFN-γ, interferon gamma; IL, interleukin; ILC1, type 1 innate lymphoid cell; ILC2, type 2 innate lymphoid cell; M1, type 1 macrophage; M2, type 2 macrophage; NE, norepinephrine; T-bet, t-box transcription factor TBX21; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cell.

Figure 2

Immunometabolism and Lipid Processing in ILC2s. ILC2s preferentially utilize fatty acid oxidation for their proliferation and cytokine secretion. In order to survive in the adipose tissue, ILC2s avoid lipotoxicity via storage of free fatty acids in lipid droplets. This process is regulated by the energy sensor mTOR which controls PPARγ and DGAT1 which ILC2s use to store fatty acids in droplets. mTOR is largely regulated by the abundance of glucose imported by Glut1. ILC2s then increase oxidative phosphorylation for their production of energy to enhance their function. When lipid processing is impaired, free fatty acids accumulate heavily in adipose ILC2s leading to lipotoxicity and diminished function. This can be caused by deficiencies in PPARγ or DGAT1. In addition, ILC2s intake more glucose and increase glycolysis as they are unable to utilize fatty acids effectively. This immunometabolic switch leads to decreased effector function and survival of ILC2s. Glut1, glucose transporter 1; IL, interleukin; IL-33R, IL1rl1; ILC2, type 2 innate lymphoid cell; mTOR, mammalian target of rapamycin; TCA cycle, citric acid cycle.

Figure 3

ILC2 Trafficking and Maintenance in Adipose Tissue. ILC progenitors are able to traffic from the bone marrow to their resident tissue to replenish and restore type 2 responses. In the blood, cytokine levels affect the outcome of these progenitors due to their natural plasticity. ILC progenitors exposed to high IFN, TNF-α, IL-1β, and IL-12 will develop into ILC1s. While ILC2s could still develop, high IFN-α/β/γ levels greatly decrease the effector function of ILC2s rendering them inactive. Once arrived in the adipose tissues, low IL-33 and PGD2 effects the number and function of ILC2s. High TNF-α, IL-1β, IL-33, and PGD₂ generate active ILC2s able to protect adipose from dysfunction responsible for T2DM. IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; ILC1, type 1 innate lymphoid cell; ILC2, type 2 innate lymphoid cell; PGD₂, prostaglandin D2; T-bet, t-box transcription factor TBX21; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cell.