Abstract
Systemic oxygen restriction (SOR) is prevalent in numerous clinical conditions, including chronic obstructive pulmonary disease (COPD), and is associated with increased susceptibility to viral infections. However, the influence of SOR on T cell immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial-biogenesis in activated mouse CD8+ T cells. We find that low oxygen level diminishes CD8+ T cell anti-viral response in vivo. We reveal that respiratory restriction inhibits ATP-dependent matrix processes that are critical for mitochondrial-biogenesis. This respiratory restriction-mediated effect could be rescued by TCA cycle re-stimulation, which yielded increased mitochondrial matrix-localized ATP via substrate-level phosphorylation. Finally, we demonstrate that the hypoxia-arrested CD8+ T cell anti-viral response could be rescued in vivo through brief exposure to atmospheric oxygen pressure. Overall, these findings elucidate the detrimental effect of hypoxia on mitochondrial-biogenesis in activated CD8+ T cells, and suggest a new approach for reducing viral infections in COPD.
Highlights
It is presently unclear exactly how CD8+ T cell response is influenced by systemic oxygen restriction (SOR)
To assess how respiratory restriction influences the levels of different phospho-nucleotides, we examined the metabolic profiles of oligomycin-treated T-Early and time-points later than hr post-stimuli (T-Late) cells compared to untreated controls
The response to oligomycin was comparable between T-Early and T-Late cells (Figure 3C). These results suggest that despite the important role of AMPK signaling in T cell metabolic adaptation (Blagih et al, 2015), it is not correlated with the inhibitory effects mediated by respiratory restriction in early activation
Summary
It is presently unclear exactly how CD8+ T cell response is influenced by systemic oxygen restriction (SOR) This subject is difficult to investigate as it requires the identification of specific metabolic effects within the dynamic system of activated cells in a process of rapid transformation and rewiring (MacIver et al, 2013). This is important field of research, since hypoxemia, reduced blood oxygen saturation, and tissue hypoxia are associated with multiple respiratory and circulatory diseases, including chronic obstructive pulmonary disease (COPD) and congenital heart disease (Kent et al, 2011; Kaskinen et al, 2016; O’Brien and Smith, 1994). This is interesting because activated T cells undergo an early shift in cell metabolism, in parallel to activation stimuli, switching to aerobic glycolysis to support their expansion and cytotoxic function
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