Mitochondrial respiration is necessary for CD8⁺ T cell proliferation and cell fate

Mitochondrial electron transport chain (ETC) function is linked to the generation of ATP, signaling molecules including reactive oxygen species (ROS), pyrimidines and tricarboxylic acid cycle metabolites¹. Mitochondrial electron transport is required for T cell proliferation^2-4. However, which mitochondrial ETC functions are necessary for each dynamic state of CD8⁺ T cell responses is unknown. Here we report that impairing mitochondrial complex III function, which diminishes respiration, proton pumping linked to ATP production and superoxide production, decreases peripheral naive numbers, antigen-induced CD8⁺ T cell proliferation and memory formation. Acute stimulation of mitochondrial complex III-deficient CD8⁺ T cells induced an exhausted-like phenotype. Expression of Ciona intestinalis alternative oxidase (AOX) in mitochondrial complex III-deficient CD8⁺ T cells restores respiration without generating ROS or proton pumping, and rescues proliferation and the exhausted phenotype but not naive or memory formation. Thus, T cell development, proliferation and memory formation have distinct requirements for mitochondrial complex III ROS.