Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix substrate-level phosphorylation arrest

Abstract

SUMMARYSystemic oxygen restriction (SOR) is prevalent in numerous clinical conditions including chronic obstructive pulmonary disease (COPD). However, the influence of SOR on T cell protective immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells. We find that low oxygen diminishes CD8+ T cell viral response in vivo. Using genetic and pharmacological models, we demonstrate that respiratory restriction inhibits ATP dependent matrix processes, all critical for mitochondrial biogenesis. The effect mediated by respiratory restriction could be rescued by TCA cycle re-stimulation, which led to increased mitochondrial matrix localized ATP via substrate-level phosphorylation. Finally, we demonstrate that short exposure to atmospheric oxygen pressure rescues the CD8+ viral response under systemic oxygen restriction in vivo. Our findings reveal the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells and provide a new approach for reducing viral infections in COPD.HighlightsSystemic chronic hypoxia compromises CD8+ T cell activationShortly upon activation, T cells’ cytoplasmic activity becomes independent of mitochondrial ATP outfluxRespiratory-blockade arrests mitochondrial remodeling due to energy depletionUncoupler-based TCA stimulation rescues respiratory-restricted activated CD8+ T cells by stimulating matrix localized substrate-level phosphorylationCD8+ T cell arrest due to hypoxia in vivo can be rescued by short exposure to atmospheric oxygen pressure.