6.2 T Cell Exhaustion
T cell exhaustion refers to the impaired T cell activity seen in persistent infections and malignancies. This condition is marked by a gradual decline in T cell function, eventually resulting in a total lack of cascade effects109. New research has shown elevated levels of cytotoxic and T helper cell exhaustion in individuals diagnosed with T2DM110. A study examining the association between programmed cell death 1 and its ligand (PD-1/PD-L1) in T2DM and macrovascular lesions, demonstrated that PD-1 levels were higher in individuals diagnosed with T2DM than the control group111. The first phase of T cell exhaustion is characterized by a decrease in IL-2 production and PD-1 expression, followed by defective TNF production. Some cytotoxic effector function is regained in the middle stage, and cells eventually have high PD-1 expression112. The combination of T cell activation and exhaustion may seem to be contradictory, but they can co-exist in a certain disease state, suggesting that at least partial T cell exhaustion is present in patients with T2DM.
T-cell exhaustion occurs primarily in cancer, chronic infections, and autoimmune diseases. As a result of prolonged exposure to persistent antigens and inflammation, T cells are activated to form early exhausted T cells, which maintain some degree of effector capacity and proliferation. As activation continues, early exhausted T cells gradually lose their effector function, are unable to differentiate into memory cells, and ultimately lose their proliferative and effector capacities altogether113. Studies on the PD-1/PD-L1 pathway in T2DM have found that PD-1 expression is downregulated in individuals with T2DM and that it is positively correlated with insulin and diabetes duration and negatively correlated with BMI114. With aging and disease progression, individuals with T2DM show a decreasing total number of CD4+ and CD8+ T cells, reduced differentiation of naïve T cells, and immune senescence and depletion. Therefore, the stimulation and subsequent exhaustion of T cells are significant factors in the pathogenesis of T2DM, ultimately leading to full T-cell depletion as the illness progresses.