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Original research
Extracellular mitochondria drive CD8 T cell dysfunction in trauma by upregulating CD39
  1. Shilpa Tiwari-Heckler1,2,3,
  2. Ghee Rye Lee4,
  3. James Harbison4,
  4. Carola Ledderose4,
  5. Eva Csizmadia4,
  6. David Melton2,
  7. Quanzhi Zhang5,
  8. Wolfgang Junger4,
  9. Guanqing Chen2,
  10. Carl J Hauser4,
  11. Leo E Otterbein4,
  12. Maria Serena Longhi2,
  13. Simon Christopher Robson2,3
  1. 1Gastroenterology, University Hospital Heidelberg Medical Clinic, Heidelberg, Germany
  2. 2Center for Inflammation Research, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  3. 3Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  4. 4Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  5. 5Harbin Medical University, Harbin, China
  1. Correspondence to Professor Simon Christopher Robson, Center for Inflammation Research, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; srobson{at}bidmc.harvard.edu

Abstract

Rationale The increased mortality and morbidity seen in critically injured patients appears associated with systemic inflammatory response syndrome (SIRS) and immune dysfunction, which ultimately predisposes to infection. Mitochondria released by injury could generate danger molecules, for example, ATP, which in turn would be rapidly scavenged by ectonucleotidases, expressed on regulatory immune cells.

Objective To determine the association between circulating mitochondria, purinergic signalling and immune dysfunction after trauma.

Methods We tested the impact of hepatocyte-derived free mitochondria on blood-derived and lung-derived CD8 T cells in vitro and in experimental mouse models in vivo. In parallel, immune phenotypic analyses were conducted on blood-derived CD8 T cells obtained from trauma patients.

Results Isolated intact mitochondria are functional and generate ATP ex vivo. Extracellular mitochondria perturb CD8+ T cells in co-culture, inducing select features of immune exhaustion in vitro. These effects are modulated by scavenging ATP, modelled by addition of apyrase in vitro. Injection of intact mitochondria into recipient mice markedly upregulates the ectonucleotidase CD39, and other immune checkpoint markers in circulating CD8+ T cells. We note that mice injected with mitochondria, prior to instilling bacteria into the lung, exhibit more severe lung injury, characterised by elevated neutrophil influx and by changes in CD8+ T cell cytotoxic capacity. Importantly, the development of SIRS in injured humans, is likewise associated with disordered purinergic signalling and CD8 T cell dysfunction.

Conclusion These studies in experimental models and in a cohort of trauma patients reveal important associations between extracellular mitochondria, aberrant purinergic signalling and immune dysfunction. These pathogenic factors with immune exhaustion are linked to SIRS and could be targeted therapeutically.

  • Bacterial Infection
  • Critical Care
  • Pneumonia
  • Emergency Medicine

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • MSL and SCR are joint senior authors.

  • Contributors ST-H, GC, MSL, SCR: acquisition of data, analysis and interpretation of data, drafting of the manuscript. GRL, JH, EC, CL, QZ: acquisition of data. DM, WJ, CJH, LEO: critical revision of the manuscript. ST-H, MSL, SCR: writing of the manuscript. SCR: guarantor. All authors have read the manuscript and approved the final version.

  • Funding The study was supported by the German Research Foundation (DFG TI-988/1-1 to ST-H), National Institutes of Health (HD-098363, GM-116162, and GM-136429 to WJ, R01 DK108894 and R01 DK124408 to MSL and R21 CA164970 to SCR) and the Department of Defense Award W81XWH-16-0464 (to SCR, CJH and LEO).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.