MEK-dependent bioenergetic demand drives terminal CD8⁺ T cell exhaustion.

ABSTRACT: Loss of mitochondrial function contributes to CD8⁺ T cell dysfunction during persistent antigen encounter. How chronic antigen leads to this metabolic dysfunction remains unclear. Here, we show that TCR-dependent mitochondrial NADH accumulation drives production of ROS, ultimately leading to mitochondrial dysfunction. Among TCR-dependent proximal signaling components, MEK inhibition uniquely reduced nutrient uptake and mitochondrial NADH accumulation while increasing proliferation. As a result, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, we found that chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEK inhibition reversed chronic TCR stimulat

SUBMITTER: Mitra T 

PROVIDER: S-EPMC12247870 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature