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.