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Hepatology
Original research
Opposite regulation of intestinal and intrahepatic CD8+ T cells controls alcohol-associated liver disease progression
  1. Luca Maccioni1,2,
  2. Yukun Guan1,
  3. Mariia Kim3,
  4. Maria A Parra4,
  5. Brandon Peiffer4,
  6. Yaojie Fu1,
  7. Yang Wang1,
  8. Yu-Hong Lin1,
  9. Bryan Mackowiak1,
  10. Dechun Feng1,
  11. Andrew Cameron5,
  12. Zhaoli Sun4,
  13. George Kunos2,
  14. Peter Stärkel6,7,
  15. Bin Gao1
  1. 1Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
  2. 2Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
  3. 3Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia, USA
  4. 4Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  5. 5Surgery - Division of Transplant Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  6. 6Department of Hepato-Gastroenterology, Cliniques universitaires Saint-Luc, Bruxelles, Belgium
  7. 7Laboratory of Hepato-gastroenterology (GAEN), Institute of Experimental and Clinical Research, UCLouvain, Brussels, Belgium
  1. Correspondence to Dr Bin Gao; bgao{at}mail.nih.gov

Abstract

Background Gut-liver crosstalk plays an important role in alcohol-associated liver disease (ALD) pathogenesis; but underlying mechanisms remain obscure.

Objective We examined the regulation of intestinal and intrahepatic CD8+ T lymphocytes and their contribution to ALD.

Design ALD patients were recruited for evaluation of intestinal and liver T cells. Single-cell RNA sequencing (scRNA seq) was performed to analyse intrahepatic and peripheral T cells in ALD. Wildtype, CD8-specific Bcl2 transgenic (Cd8Bcl-2), and Cd8−/− mice were subjected to chronic-plus-binge ethanol feeding.

Results In ALD patients, duodenal CD8+ T cells were selectively reduced and negatively correlated with liver injury and bacterial translocation markers, while intrahepatic CD8+ T cells were markedly increased. ScRNA seq analysis of ALD patient livers revealed several populations of CD8+ T cells expressing activation and survival genes (eg, Bcl2). Transcriptomics and functional studies revealed a key role of prosurvival BCL2 in this opposite regulation of CD8+ T cells. Mechanistically, chronic-plus-binge ethanol feeding reduced CD8+ T cells specifically in the duodenum where ethanol levels are high. Inducing BCL2 in CD8+ T cells reversed ethanol-induced loss of duodenal CD8+ T cells, improved gut barrier function and ameliorated ALD, while CD8 deficiency was linked to enhanced neutrophil and macrophage infiltration in the liver, exacerbating ALD in mice.

Conclusions ALD is associated with loss of duodenal CD8+ T cells but elevation of intrahepatic CD8+ T cells, which aggravates and ameliorates ALD, respectively. Restoration of survival and functions of intestinal and intrahepatic CD8+ T cells may represent a novel therapeutic strategy for ALD patients.

  • T LYMPHOCYTES
  • ALCOHOLIC LIVER DISEASE

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Some of the data are available on reasonable request.

https://doi.org/10.1136/gutjnl-2024-334412

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. Some of the data are available on reasonable request.

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    Footnotes

    • Contributors LM: guarantor of the manuscript; conceptualise, design and execute the research; draft, edit and revise manuscript; take responsibility of the research. YG, MK, MAP, BP, YF, YW, Y-HL, BM, DF, AC, ZS, GK and PS: execute part of the research; edit and revise the manuscript. BG: conceptualise, design and execute the research; draft, edit and revise manuscript; take responsibility and supervise the research.

    • Funding The work was supported by the intramural programme of the NIAAA, NIH (AA00350 to GK), (AA000369 and AA000368 to BG). The work was also supported by the NIAAA, R24AA025017 to the Johns Hopkins University. PS received grant support from the FNRS in Belgium (J.0171.21 and T.0217.18).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • 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.

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