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ResearchIn-Press PreviewImmunologyInflammationPulmonology Open Access | 10.1172/JCI192925

Maintenance DNA methylation is required for induced Treg reparative function following viral pneumonia in mice

Anthony M. Joudi,1 Jonathan K Gurkan,1 Qianli Liu,1 Elizabeth M. Steinert,1 Manuel A. Torres Acosta,1 Kathryn A. Helmin,1 Luisa Morales-Nebreda,1 Nurbek Mambetsariev,2 Carla Patricia Reyes Flores,1 Hiam Abdala-Valencia,1 Samuel E. Weinberg,3 and Benjamin D. Singer1

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

Find articles by Joudi, A. in: PubMed | Google Scholar

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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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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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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1Division of Pulmonary and Critical Care Medicine, 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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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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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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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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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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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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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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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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Published September 16, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI192925.
Copyright © 2025, Joudi et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 16, 2025 - Version history
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Abstract

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.

Graphical Abstract
graphical abstract
Supplemental material

View Supplemental Table 1. DEG lists used to generate Figures 2E-F, 5B-C, 6D, Supplemental 3A, Supplemental 7B-E. Provided as a multi-tabbed Excel file.

View Supplemental Table 2. Ranked gene list used to generate Figure 2G and Supplemental Figure 3D (day 12 “delayed” Uhrf1+/+ versus day 12 “delayed” Uhrf1fl/fl iTregs) against a comprehensive list of 4,872 Immunologic Signature gene sets (Figure 2G) and 50 Hallmark gene sets (Supplemental Figure 3D) housed in the Molecular Signatures Database. [provided as a tab-delimited file]

View Supplemental Table 3. Ranked gene list used to generate Figures 5D-E (day 24 post influenza Uhrf1+/+ versus Uhrf1fl/fl iTregs) against a comprehensive list of 50 Hallmark gene sets (Figure 5D-E) and 3,930 GO Biological Process gene sets (Figure 5F) housed in the Molecular Signatures Database. [provided as a tab-delimited file]

View Supplemental Table 4. Ranked gene list used to generate Figures 6B-C (day 11 post influenza Uhrf1+/+ versus Uhrf1fl/fl iTregs) against a comprehensive list of 50 Hallmark gene sets (Figure 6B) and 3,173 GO Biological Process gene sets (Figure 6C) housed in the Molecular Signatures Database. [provided as a tab-delimited file]

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