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

  1. Amijai Saragovi
  2. Ifat Abramovitch
  3. Ibrahim Omar
  4. Eliran Arbib
  5. Ori Toker
  6. Eyal Gottlieb
  7. Michael Berger  Is a corresponding author
  1. Hebrew University, Israel
  2. Technion - Israel Institute of Technology, Israel
  3. 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

The following data sets were generated

Article and author information

Author details

  1. Amijai Saragovi

    Immunology and Cancer Research, Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Ifat Abramovitch

    The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Ibrahim Omar

    Immunology and Cancer Research, Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Eliran Arbib

    Immunology and Cancer Research, Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Ori Toker

    Department of Pediatrics, Allergy and Clinical Immunology Service, Shaare Zedek Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Eyal Gottlieb

    The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Michael Berger

    Immunology and Cancer Research, Hebrew University, Jerusalem, Israel
    For correspondence
    michaelb@ekmd.huji.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3469-0076

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

Reviewing Editor

  1. Satyajit Rath, Indian Institute of Science Education and Research (IISER), India

Publication history

  1. Received: March 3, 2020
  2. Accepted: November 21, 2020
  3. Accepted Manuscript published: November 23, 2020 (version 1)
  4. Accepted Manuscript updated: November 24, 2020 (version 2)
  5. Version of Record published: December 10, 2020 (version 3)

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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  1. Amijai Saragovi
  2. Ifat Abramovitch
  3. Ibrahim Omar
  4. Eliran Arbib
  5. Ori Toker
  6. Eyal Gottlieb
  7. Michael Berger
(2020)
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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