Maintenance DNA methylation is required for induced regulatory T cell reparative function following viral pneumonia.

Summary

In an influenza pneumonia mouse model, adoptively transferred iTregs accelerated lung recovery, but loss of UHRF1-dependent maintenance DNA methylation compromised iTreg engraftment and reparative function. Multi-omic profiling showed transcriptional instability and effector-lineage drift in UHRF1-deficient iTregs, highlighting epigenetic maintenance as a prerequisite for cell-based pro-repair therapy relevant to ARDS.

Key Findings

• Adoptive transfer of iTregs promoted lung recovery after influenza pneumonia.
• UHRF1-dependent maintenance DNA methylation was required for iTreg engraftment and reparative function.
• UHRF1-deficient iTregs exhibited transcriptional instability and gained effector T cell lineage-defining transcription factors.
• Findings support epigenetic stabilization strategies to augment iTreg-based pro-repair therapies in viral pneumonia and ARDS.

Clinical Implications

Stabilizing iTregs via epigenetic modulation (e.g., preserving UHRF1 function) could enhance future cell-based therapies for viral pneumonia–related ARDS; biomarkers of iTreg stability may guide candidate selection and dosing.

Limitations

• Preclinical mouse study limits direct generalizability to human ARDS
• Sample size and dose/kinetic parameters are not detailed in the abstract
• Preprint not yet peer reviewed

Future Directions

Develop pharmacologic or genetic approaches to sustain iTreg epigenetic stability; validate findings in human tissues and large-animal models; design early-phase trials testing iTreg therapy and biomarkers of stability in viral pneumonia–associated ARDS.