Dong LW, Ma ZC, Fu J, Huang BL, Liu FJ, Liang DC, Sun DM, Lan C. γδ T cells exacerbate intestinal fibrosis in mice with experimental colitis via activation of the CD73-adenosine receptor-cyclic AMP signaling pathway. World J Gastroenterol 2026; 32(29): 119920 [DOI: 10.3748/wjg.119920]
Corresponding Author of This Article
Cheng Lan, MD, Chief Physician, Professor, Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital of Hainan Medical University, No. 19 Xiuhua Road, Xiuying District, Haikou 570311, Hainan Province, China. lancheng71@163.com
Research Domain of This Article
Gastroenterology & Hepatology
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research-article
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Dong LW, Ma ZC, Fu J, Huang BL, Liu FJ, Liang DC, Sun DM, Lan C. γδ T cells exacerbate intestinal fibrosis in mice with experimental colitis via activation of the CD73-adenosine receptor-cyclic AMP signaling pathway. World J Gastroenterol 2026; 32(29): 119920 [DOI: 10.3748/wjg.119920]
Li-Wei Dong, Zhi-Chao Ma, Jiao Fu, Bai-Li Huang, Fu-Jin Liu, Cheng Lan, Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital of Hainan Medical University, Haikou 570311, Hainan Province, China
Dong-Chun Liang, De-Ming Sun, Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90033, United States
Author contributions: Liang DC performed most of the experiments; Ma ZC, Fu J, and Huang BL analyzed the data; Dong LW provided technique support; Sun DM and Liu FJ supervised experiment and wrote the manuscript; Lan C supervised and coordinated the project.
Supported by the National Natural Science Foundation of China, No. 81860102 and No. 82060102; and Hainan Provincial Natural Science Foundation High-Level Talent Project, No. 821RC1116 and No. 822RC818.
Institutional animal care and use committee statement: The experimental protocol was approved by the Animal Care and Use Committee of Hubei Provincial Center for Disease Control and Prevention (No. 202210177).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Corresponding author: Cheng Lan, MD, Chief Physician, Professor, Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital of Hainan Medical University, No. 19 Xiuhua Road, Xiuying District, Haikou 570311, Hainan Province, China. lancheng71@163.com
Received: February 10, 2026 Revised: March 17, 2026 Accepted: April 20, 2026 Published online: August 7, 2026 Processing time: 156 Days and 23.3 Hours
Abstract
BACKGROUND
Intestinal fibrosis is a prevalent complication of chronic inflammatory bowel disease, affecting approximately one-third of patients with Crohn’s diseases. It represents a leading cause of stricture formation, luminal obstruction, and surgical intervention. Despite its clinical significance, no approved anti-fibrotic therapies are currently available, and the underlying pathogenic mechanisms remain incompletely understood. Although γδ T cells, a major population of innate-like T lymphocytes in the intestine, have been implicated in pulmonary and liver fibrosis, their functional role in intestinal fibrosis has not been elucidated.
AIM
To investigate how CD73 modulates the innate immune function of γδ T cells in a mouse model of experimental intestinal fibrosis.
METHODS
Intestinal fibrosis was induced in mice using chronic 2,4,6-trinitrobenzenesulfonic acid administration. The pathogenic role of γδ T cells was assessed via antibody-mediated depletion (GL3) and adoptive transfer. The involvement of the CD73-adenosine receptor-cyclic AMP (cAMP) axis was validated through pharmacological intervention using specific inhibitors (PSB-12379, SQ22536) and activators (forskolin).
RESULTS
In the 2,4,6-trinitrobenzenesulfonic acid-induced intestinal fibrosis model, antibody-mediated depletion of γδ T cells ameliorated fibrosis, evidenced by reduced clinical scores, decreased extracellular matrix deposition, attenuated pro-fibrotic cytokine levels, and elevated anti-fibrotic cytokines. Conversely, reinfusion of γδ T cells significantly exacerbated intestinal fibrosis. Mechanistically, γδ T cell depletion downregulated CD73 expression in fibrotic mice, and pharmacological CD73 inhibition similarly attenuated fibrosis. Interventions targeting the CD73-cAMP signaling pathway using cAMP activators and antagonists correspondingly attenuated or exacerbated intestinal fibrosis.
CONCLUSION
This study identifies γδ T cells as pivotal drivers of intestinal fibrosis via the upregulation of the CD73-adenosine receptor-cAMP signaling pathway. Targeting this axis offers a promising therapeutic strategy for fibrostenotic Crohn’s disease.
Core Tip: This study elucidated a critical pathogenic role for γδ T cells in driving intestinal fibrosis. Mechanistically, these cells promote fibrosis most likely by upregulating the CD73-adenosine receptor-cyclic AMP signaling pathway. Depletion of γδ T cells or pharmacological inhibition of CD73 attenuated fibrogenesis, as evidenced by reduced collagen deposition and profibrotic cytokine expression. Conversely, adoptive transfer of γδ T cells exacerbated disease severity. These findings nominate the γδ T cell-CD73-adenosine receptor-cyclic AMP pathway as a novel and promising therapeutic target for intestinal fibrosis.
