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

CD8 T cell proliferation and memory formation are linked to changes in metabolism, which has important implications for improving CD8 T cell fitness in therapies against chronic infections and cancer. The mitochondrial electron transport chain (ETC) is essential for antigen-specific CD8 T cell proliferation. Mitochondrial ETC function is linked to the generation of ATP, production of metabolites to sustain proliferation, and signaling molecules including reactive oxygen species (ROS), which determine T cell function and fate. However, it is not fully understood which mitochondrial ETC functions are necessary for CD8 T cell proliferation in vivo. Here we report that impairing mitochondrial complex III function, which diminishes respiration, proton pumping linked to ATP production, and superoxide production, decreases CD8 T cell proliferation and memory formation. CD8 T cells lacking functional mitochondrial complex III also exhibit an exhausted-like phenotype following acute stimulation. The expression of Ciona intestinalis alternative oxidase (AOX), which accepts electrons from coenzyme Q, thus compensating for the loss of mitochondrial complex III function without generating ROS or proton pumping, restores respiration, proliferation and largely prevents the exhausted phenotype in vitro and in vivo. However, AOX did not sustain memory CD8 T cells, suggesting mitochondrial complex III ROS is necessary for optimal memory formation. These findings demonstrate that the primary function of the mitochondrial ETC in CD8 T cells is enabling respiration to sustain proliferation and memory formation as well as to prevent an exhausted phenotype.