6.1 T Cell Activation
Primary T cells enter the circulation after thymic development and
maturation and are recognized by the MHC under initial and repeated
antigenic stimulation. T cells interact with APC to induce the
proliferation and differentiation of effector T cells and long-lived
memory cells and the release of cytokines by effector T cells to kill
specific antigens103, a process known as T cell
activation or cellular immunity. T2DM is a chronic, low-grade
inflammatory disease caused by IR, hyperglycemia, and the persistent
stimulation of immune cells, including macrophages, mast cells, and T
cells. During obesity, excessive levels of free fatty acids and glucose
stimulate an increase in the number and activity of T cells in
islet-sensitive tissues (especially adipose, liver, and muscle tissues),
accompanied by the accumulation and polarization of
macrophages104. Reduced insulin sensitivity results
from the accumulation of activated immune cells in tissues and the
production of pro-inflammatory cytokines that then interact with nearby
insulin target cells9. In general, Th1 cells, and Th17
cells increase inflammation and IR, whereas Th2 and Treg have a
suppressive role104, based on the context and level of
disease development.
The bidirectional interaction between T2DM and inflammation is achieved
through immune cell regulation (Figure 2). In diabetes, high levels of
blood glucose react with proteins to form advanced glycosylation
end-products (AGEs), which AGEs upregulate electrogenic
Ca2+-activated K+ channels to
promote peripheral blood mononuclear cell (PBMC) migration, participate
in T and B cell activation, and are positively correlated with glycated
hemoglobin (HbA1c) levels105. In addition, AGEs
promote the emission of inflammation-related mediators via the control
of pathways such as PI3K/AKT, and prolonged exposure to inflammatory
factors ultimately leads to blockage of insulin signaling receptors and
exacerbates hyperglycemia105,106. In addition,
HFD-induced obesity leads to dysregulation of Th17/Treg homeostasis
through the TGFβ1/IRF3/STAT3 pathway, which promotes the release of Th1
cytokines, facilitates macrophage conversion to the M1 type, and
exacerbates inflammation and IR107 (Figure 3). Obesity
and diabetes disrupt adaptive immune homeostasis, activate T cells to
proliferate toward pro-inflammatory phenotypes, and release inflammatory
factors and chemokines to exacerbate the course of the disease. However,
T cell activation is dependent on lactate production from aerobic
glycolysis, and the addition of lactate during T cell differentiation
can activate the AKT/mTOR signaling, promote T cell differentiation
toward Tregs, and inhibit Th1 cell differentiation90.
Therefore, the full utilization of glucose to promote increased lactate
production during hyperglycemia may serve as a feedback mechanism to
limit inflammatory diseases. Conversely, it has been suggested that
hyperglycemia interferes with calcium transduction signaling and
prevents T cell activation108. Therefore, T cell
activation and T cell immunity in T2DM are unclear, and how T cell
subsets and pro-inflammatory or anti-inflammatory factors are
distributed during T cell activation needs to be explored.