4.1 Th2 Cells
Unlike Th1 cells, Th2 cells mainly play an anti-inflammatory role. They
were initially discovered for their importance in warding off parasitic
illnesses63. GATA binding protein 3 is a major
regulatory gene for Th2 cells, producing cytokines such as IL-5, IL-10,
and IL-13, and IL-4 by activating STAT5 and
STAT658,63. Antigen dose and T cell receptor-mediated
signaling intensity correlate with the generation of Th1 and Th2 cells
during differentiation64, with low or moderate doses
of antigen promoting a dominant Th1 cell response and high doses of
antigen favoring Th2 cell production65. IL-4 was the
first stimulant identified to be produced by M2-type
macrophages66 and has an inhibitory effect on
inflammation.
The proportion of IL-4 is significantly decreased in both the adipose
tissue and peripheral blood of obese mice and the reduction in IL-4 is
accompanied by IFN-γ-associated aggregation of Th1
cells58,67,68. Increased numbers of pro-inflammatory
cells due to visceral adiposity and obesity are important drivers of IR
and the development of T2DM. Th2 cells maintain adipose metabolic
homeostasis by secreting IL-4 and IL-13, which induce an M2-like,
anti-inflammatory state in macrophages associated with adipose
tissue69. Furthermore, CD4+ T cell
transfer into lymphocyte-depleted Rag1 deleted mice with diet-induced
obesity reduces weight gain and improves insulin sensitivity, mostly
owing to an increase in the proportion of Th2 cells27;
however, an equivalent effect can not be produced in mice with impaired
Th2 cell development70, indicating that Th2 cells play
an essential role in mitigating obesity and IR.
Similarly, in humans, individuals with overweight or obesity have
reduced Th2 cells, and Th2 cells in the visceral adiposity and
peripheral blood are negatively associated with systemic IR and plasma
high-sensitivity C-reactive protein69.
Mechanistically, Th2 cells enhance glucose utilization by producing IL-4
polarized macrophages, increase peroxisome proliferator-activated
receptor gamma (PPARγ) driven GLUT4 expression71, and
activate the mechanistic target of the rapamycin complex (mTORC)2
pathway72. In addition, IL-13 activation by JUN-STAT
induces growth differentiation factor 15 expression to ameliorate poor
glucose tolerance73. Therefore, an increase in Th2
cytokines is closely linked to the classical insulin signaling pathway
and macrophage polarization, which protect against disease progression
by enhancing glucose sensitivity and anti-inflammatory properties.