ORIGINAL RESEARCH article
Front. Immunol.
Sec. T Cell Biology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1601637
CD39 Dynamics in Tuberculosis: A Potential Biomarker of Immune Dysregulation and T Cell Exhaustion
Provisionally accepted
- 1Department of Pulmonary and Critical Care Medicine, Guangzhou First People's Hospital, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- 2Institute of Clinical Medicine, Guangzhou First People's Hospital, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- 3Department of Clinical Microbiology, Umeå University, Umeå, Sweden
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Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health crisis complicated by immune dysregulation and T cell exhaustion. CD39, an ectonucleotidase generating immunosuppressive adenosine, is implicated in cancer and chronic infections, yet its spatiotemporal role in TB pathogenesis remains unclear. Methods: Multiple publicly available datasets were utilized to evaluate CD39 across TB disease stages, diverse infectious diseases and anti-TB treatment. Diagnostic accuracy was evaluated via ROC curves and combined signature analysis. Immune cell infiltration were analyzed using CIBERSORTx. Cytokine profiles and age-stratified associations were examined. Pathway enrichment analysis was performed by GSEA. Single-cell analysis of non-human primate granulomas assessed CD39’s temporal dynamics, utilizing Monocle 3 for CD39+ T-cell trajectory analysis. Results: CD39 was upregulated in active TB patients versus TB infection (TBI) and healthy controls (HC), correlating with older age, disease severity, and distinct expression patterns compared to other respiratory and systemic infections. CD39 demonstrated superior diagnostic accuracy over IFN-γ in distinguishing TB from TBI/HC and other respiratory diseases. Combining CD39 with TBX21 or GZMB further improved diagnostic specificity. High CD39 correlated with suppressed Th1 and elevated Th2/Th17/regulatory cytokines, alongside pronounced neutrophil infiltration. Age-stratified analysis revealed complex age-dependent associations of CD39 expression with various immune cell types. Single-cell analysis revealed declining CD39 transcriptional activity during prolonged infection despite expanded cellular distribution, linked to early T cell maturation followed by broader immunomodulatory shifts. Decreased CD39 expression with anti-TB treatment correlated with improved immune cell balance and resolved T cell exhaustion. Conclusion: CD39 was a critical regulator of immune exhaustion and neutrophil-driven inflammation in TB, with diagnostic and therapeutic potential. Targeting CD39 may provide a novel therapeutic strategy for TB.
Keywords: ENTPD1, CD39, Tuberculosis, Immune dysregulation, t cell exhaustion, inhibitory receptors
Received: 01 Apr 2025; Accepted: 18 Jul 2025.
Copyright: © 2025 Hao and Ullah. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ling Hao, Department of Pulmonary and Critical Care Medicine, Guangzhou First People's Hospital, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
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