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.