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Open Access | 10.1172/JCI192925
1Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Division of Allergy and Immunology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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2Division of Allergy and Immunology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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3Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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3Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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3Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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3Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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Published September 16, 2025 - More info
FOXP3+ natural regulatory T cells (nTregs) promote resolution of inflammation and repair of epithelial damage following viral pneumonia-induced lung injury, thus representing a cellular therapy for patients with severe viral pneumonia and the acute respiratory distress syndrome (ARDS). Whether in vitro induced Tregs (iTregs), which can be rapidly generated in substantial numbers from conventional T cells, also promote lung recovery is unknown. nTregs require specific DNA methylation patterns maintained by the epigenetic regulator, ubiquitin-like with PHD and RING finger domains 1 (UHRF1). Here, we tested whether iTregs promote recovery following viral pneumonia and whether iTregs require UHRF1 for their pro-recovery function. We found that adoptive transfer of iTregs to mice with influenza virus pneumonia promotes lung recovery and that loss of UHRF1-mediated maintenance DNA methylation in iTregs leads to reduced engraftment and a delayed repair response. Transcriptional and DNA methylation profiling of adoptively transferred UHRF1-deficient iTregs that had trafficked to influenza-injured lungs demonstrated transcriptional instability with gain of effector T cell lineage-defining transcription factors. Strategies to promote the stability of iTregs could be leveraged to further augment their pro-recovery function during viral pneumonia and other causes of severe lung injury.