Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate
Elizabeth M. Steinert, Beatriz Furtado Bruza, Veronika Denise Danchine, Rogan A. Grant, Karthik Vasan, Arjun Kharel, Yuqi Zhang, Weiguo Cui, Marten Szibor, Samuel E. Weinberg, Navdeep S. Chandel
Abstract
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 proliferation2–4. 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. Mitochondrial electron transport chain activity provides ATP, generates superoxide, regulates apoptosis and provides the biosynthetic building blocks for growing cells. Here Steinert et al. genetically dissect these functions and find that, in the absence of mitochondrial complex III function, acute stimulation results in CD8+ T cell exhaustion and that mitochondrial complex III reactive oxygen species are required for establishment of naive and memory populations.