Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix substrate-level phosphorylation arrest
- Hebrew University, Israel
- Technion - Israel Institute of Technology, Israel
- Shaare Zedek Medical Center, Israel
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 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+ 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.
Data availability
Metabolic analysis data and Protein MS analysis have been deposited in OSF under DOI 10.17605/OSF.IO/JKMQF
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MS analysis of anti-ubiquitin precipitated proteins from oligomycin treated T cellsDOI 10.17605/OSF.IO/JKMQF.
Article and author information
Author details
Funding
Israeli Science Foundation (Personal grant,1596/17)
- Michael Berger
German Israeli Foundation for Scientific Research and Development (I-1474-414.13/2018)
- Michael Berger
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the guidelines of the institutional ethics committee (AAALAC standard). The protocols were approved by the Committee on the Ethics of Animal Experiments of the Hebrew University (Ethics Committee - research number: MD-16-14863-1 and MD-18-15662-5). Every effort was made to minimize suffering.
Human subjects: Human blood samples were obtained via Shaare Zedek Medical Center Jerusalem, Helsinki committee approval number: 143/14
Copyright
© 2020, Saragovi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix substrate-level phosphorylation arrest
eLife 9:e56612.
https://doi.org/10.7554/eLife.56612
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