Compensatory electron transfer from the ubiquinol pool circumvents cytochrome c oxidase deficiency and restores effector and memory T cell function

The ultimate goal of immunometabolism is to modulate metabolic pathways to enhance immunity. Here, we investigate the potential of an alternative oxidase (AOX) to counteract cytochrome c oxidase (COX) deficiency in T cells. COX is vital for oxidative phosphorylation (OXPHOS), and its deficiency leads to redox imbalances, impaired metabolism, reactive oxygen species (ROS), and apoptosis, resulting in T cell immunodeficiency. We introduced an AOX into COX-deficient T cells, which revealed a normalization of genes involved in redox balance, apoptosis, and metabolic pathways. Mitochondrial function, glycolysis and TCA cycle function were also restored. AOX-enhanced T cells showed improved activation, proliferation, differentiation, and memory formation, resulting in better immune responses against viral challenges. These findings suggest that targeting the ubiquinol pool could be a promising therapeutic strategy for enhancing T cell function in conditions characterized by COX dysfunction and compromised immune responses. This study includes read counts from two RNAseq experiments. In the first experiment, RNA was derived from T cells from four groups of mice on a C57Bl/6J background: wildtype (WT), Cox10fl/fl;Cd4-Cre (TCox10-/-), Rosa26-targeted Ciona intestinalis alternative oxidase expressing (Aox), and TCox10-/-/Aox double mutants. The goal of this experiment was to evaluate the ability of AOX to compensate for COX deficiencies in T cells. In the second experiment, RNA is derived from T cells from two groups of mice on a C57BL/6-Tg(TcraTcrb)1100Mjb/J (OT-1) background: wildtype (WT_IL15), and TCox10-/-/Aox double mutants (TCox10-/-/Aox_IL15). The goal of this experiment was to evaluate the ability of AOX to compensate for COX deficiencies in memory T cells. *************************************************************** Submitter states that missing raw files are due to file loss. ***************************************************************