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.