3.1 Th1 Cells
Th1 cells were first identified from mice in 198624. They release mainly TNF-α and IL-225. Their activation and repopulation are dependent on the co-stimulation of CD28 on the cell surface26, and they participate in cellular immunity and mediate inflammatory responses. Early studies indicated increased IFN-γ secretion by Th1 cells in the visceral adipose tissue of obese mice, leading to disruption of glucose homeostasis and promoting IR in vivo27. Further studies have demonstrated that individuals with IR, hyperglycemia, and dyslipidemia have significantly higher levels of Th1 cells in their peripheral blood28. IFN-γ-related immune responses are involved in diabetic ketoacidosis, leading to a transient decline in β cell function and an increase in disease activity29. However, there is controversy as to whether IL-2 is elevated in individuals with T2DM30–32, suggesting that IFN-γ is a key link in the Th1-mediated immune response to obesity and related metabolic syndromes.
Chronic IFN-γ expression mouse model (ARE-Del-/-) overlaps with upstream regulatory genes, such as toll-like receptor (TLR) 4, when mice are fed a high-fat diet (HFD). These mice also induce both innate and adaptive immunity involved in hepatic inflammation33, suggesting that IFN-γ-mediated inflammatory responses may crosstalk with TLR4-related inflammatory signaling. TLRs are an important class of receptors involved in innate immunity and an important bridge between adaptive and innate immunity. TLR4 expression is associated with elevated IFN-γ and promotes IR in individuals with T2DM34. IFN-γ inhibits the expression of insulin-related signaling genes, significantly reduces glucose transporter type 4 (GLUT4), insulin receptor, and insulin substrate (IRS)-1 levels, and decreases glucose uptake. Mechanistic studies revealed that IFN-γ activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway to reduce insulin sensitivity and inhibit adipocyte differentiation35(Table 1). In addition, IFN-γ promotion of adipocyte apoptosis and IR is dependent on stimulation of the T cell co-stimulatory factor CD80 by liver kinase B1 (LKB1)36. Direct substrates of LKB1, including AMP-activated protein kinase (AMPK), are key for maintaining metabolism and reducing oxidative stress37. Th1 activation relies on the regulation of metabolic stress, which in turn promotes pathological metabolic states. Th1 cells have important roles in adipose and insulin homeostasis, possibly through the secretion of IFN-γ. However, the mechanisms associated with other Th1 cytokines involved in lipid and glucose homeostasis have not yet been elucidated.
TABLE 1 Role of T cell subsets on T2DM proteins.