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.