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Antisense to human CD39 dysregulates immune metabolism in inflammatory bowel disease

Cellular & Molecular Immunology volume 22, pages 730–742 (2025)Cite this article

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A Comment to this article was published on 24 June 2025

Abstract

Defective CD39 levels contribute to an imbalance between Tregs and Th17 effectors in inflammatory bowel disease (IBD). CD39 initiates an ATP hydrolysis cascade that culminates with the generation of adenosine, an immune metabolite that is key to tissue homeostasis. Human CD39 is regulated by an endogenous antisense RNA (CD39-AS) that is markedly elevated in IBD Tregs and Th17 cells. In this study, we investigated how CD39-AS affects the function of Tregs and Th17 cells in healthy subjects and IBD patients. We report that CD39-AS RNA is present in two main splice variants that are specifically expressed by Tregs or Th17 cells. Blockade of CD39-AS via self-delivering oligonucleotides targeting the splice variant expressed in Tregs results in a decrease of glucose transport and glycolysis and in enhanced Treg function and stability in IBD. In Th17 cells, silencing of CD39-AS limits oxidative responses and ameliorates mitochondrial health. These metabolic effects are also noted in a model of experimental colitis in humanized mice, along with reduced disease activity. Thus, in vivo administration of oligonucleotides targeting the Treg or Th17 cell CD39-AS variant limits disease activity, decreases the expression of GLUT1 and improves mitochondrial health in gut-derived CD4 lymphocytes. Mechanistically, activation of HIF-1α and STAT3 results in the upregulation of CD39-AS in IBD cells. In conclusion, CD39-AS is an important modulator of Treg and Th17 cell metabolism. Interference with this antisense RNA, or the factors favoring its upregulation, might contain inflammation and halt disease progression in IBD by restoring immune metabolism and Treg functional stability.

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Acknowledgements

This work has been supported by the National Institutes of Health (R01DK124408 to MSL; R01GM135377 to SKK); the Crohn’s and Colitis Foundation (Litwin IBD Pioneers Award to MSL); Boehringer Ingelheim Fonds MD fellowship (to DN); and grant APVV-21-0370 (to BG). The authors wish to thank the CARE Team, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, for their help with the screening and recruitment of IBD patients and controls.

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Author notes

  1. These authors contributed equally: Lina Zhang, Cortney Cagle, Du Hanh Nguyen.

Authors and Affiliations

  1. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Lina Zhang, Cortney Cagle, Du Hanh Nguyen, Graziela Scheuer Gomes, Barbora Gromova, Eva Csizmadia, Arian Karimitar, Guanqing Chen & Maria Serena Longhi

  2. School of Medicine, Tufts University, Boston, MA, USA

    Lina Zhang

  3. Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Du Hanh Nguyen

  4. Graduate Program in Pharmaceutical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

    Graziela Scheuer Gomes

  5. Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia

    Barbora Gromova

  6. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Ghee Rye Lee

  7. Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Efi Kokkotou, Laurie Grossberg & Adam S. Cheifetz

  8. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Sizun Jiang

  9. Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA

    Satya K. Kota

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Contributions

LZ, CC, DN acquired, analyzed and interpreted the data; drafted the manuscript; GGS, BG, EC acquired and analyzed the data; AK, GRL analyzed the data; GC, EK, LG, SJ, ASC and SKK critically revised the manuscript; MSL conceptualized and wrote the manuscript; MSL and SKK acquired funding.

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Correspondence to Maria Serena Longhi.

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Zhang, L., Cagle, C., Nguyen, D.H. et al. Antisense to human CD39 dysregulates immune metabolism in inflammatory bowel disease. Cell Mol Immunol 22, 730–742 (2025). https://doi.org/10.1038/s41423-025-01295-6

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