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.