Maintenance DNA methylation is required for induced Treg reparative function following viral pneumonia in mice
Year: 2025
Type: article
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. 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 transcription factors that define effector T cell lineage. 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.
DOI: 10.1172/jci192925
Institution: Northwestern University
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: G2229906039, G261961061, Epigenetic modifiers of regulatory T cell function following viral pneumonia, G3692266691, G3780152229, G4536992220, G4660062756, G4717980704, G6150573222, G659096663, G9000033877, G9000119289, G9000121372, G9000136301, G9000136738, G9000172041, G9000244833, G9000246955, G9000325779, Northwestern University Allergy and Immunology Research (NUAIR) Program, Metabolic regulation of regulatory T cells through fatty acid metabolism during viral pneumonia, The Neu-Lung Consortium: Neutrophilic Mechanisms of Inflammation, Injury, and Repair in Lung and Airways Diseases, Mechanisms of regulatory T-cell mediated endothelial repair following viral pneumonia in aged hosts
OpenAlex ID: W4414240158