Labile iron supply governs CD8+ T cell activation and function in metabolic health and obesity

Here, we find a rapid increase in the supply of labile iron in CD8+ T cells upon T-cell receptor activation. Blocking labile iron supply blunts Fe2+ influx into mitochondria and ROS production, hindering CD8+ T cell activation, while excessive labile iron content causes hyperactivation.

Disrupted labile iron supply impairs the maintenance of adipose tissue CD8+ T cells. In obesity, an increase in Fe2+ influx into mitochondria enhances adipose tissue CD8+ cell functions, but weight loss normalizes CD8+ T cell iron metabolism. CD8+ cell-specific NRF2 activation boosts ferritin and lowers mitochondrial Fe2+ and ROS content in adipose tissue CD8+ cells, attenuating obesity-related adipose tissue inflammation and metabolic disorders.