4.2 Tregs
Tregs are a well-established subset of CD4+ T cells that exhibit anti-inflammatory properties. They are characterized by the expression of CD4, CD25, and FOXP3. Tregs play a crucial role in modulating the immune response against autoimmune antigens and regulating T cell activation. They primarily secrete IL-10 and TGF-β to exert their immunomodulatory effects58,74. Tregs lack IL-6, and their differentiation is driven by TGF-β. Tregs deplete IL-2 via the high-affinity IL-2 receptor thereby inducing cytotoxic T-lymphocyte cadherin 4 (CTLA-4) expression, IL-10 production, and granzyme B secretion74. Tregs also decrease APC and effector T cells74. TGF-β serves as a shared developmental factor for both Th17 cells and Tregs, with IL-6 playing a crucial part in their differentiation process. IL-6 induces TGF-β to differentiate Th17 cells while inhibiting Tregs production under normal conditions, exacerbating the development of inflammatory and autoimmune diseases75. Several studies have shown that Tregs are abundant in healthy mouse adipose tissue but drastically diminished in obese animal models76–78. IL-10 secreted by Tregs maintains adipose tissue homeostasis by inhibiting the growth of white adipose tissue79. Tregs proliferation or over-transfer reduces adipose inflammation and ameliorates associated metabolic syndromes80–82.
Clinical studies have found that individuals with T2DM have considerably lower levels of Tregs and associated cytokines than healthy individuals83–85 and that the percentage of Tregs is negatively correlated with HOMA-IR in individuals with obesity86. Because Tregs play a role in regulating immune homeostasis and controlling the progression of metabolic syndromes, they have received increasing attention. Recently, exenatide has been shown to promote Treg proliferation by mediating the PI3K/AKT/FOXO1 pathway and reducing Th17 cells, thereby attenuating pancreatic islet inflammation87. The p38 AMPK/C/EBPβ pathway can also modulate granulocyte-macrophage colony-stimulating factor and the synthesis of IL-1088. In addition, Tregs express insulin receptors, and hyperinsulinemia inhibits IL-10 production through the activation of AKT/mTOR signaling89, which may explain a decrease in Tregs in T2DM mouse models87. However, the AKT/mTOR signaling pathway appears to have a feedback effect on T cell differentiation, and stimulation of Treg differentiation activates this pathway and increases glucose transport90. These studies have guided us toward the treatment of T2DM.