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

Joudi, A. M.; Gurkan, J. K.; Liu, Q.; Acosta, M. A. T.; Helmin, K. A.; Morales-Nebreda, L.; Mambetsariev, N.; Flores, C. P. R.; Abdala-Valencia, H.; Steinert, E. M.; Weinberg, S. E.; Singer, B. D.

doi:10.1101/2025.02.25.640199

bioRxiv · 10.1101/2025.02.25.640199

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

Joudi, A. M.·Gurkan, J. K.·Liu, Q.·Acosta, M. A. T.·Helmin, K. A.·Morales-Nebreda, L.·Mambetsariev, N.·Flores, C. P. R.·Abdala-Valencia, H.·Steinert, E. M.·Weinberg, S. E.·Singer, B. D.

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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 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 ARDS.

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Joudi, A. M., Gurkan, J. K., Liu, Q., Acosta, M. A. T., Helmin, K. A., Morales-Nebreda, L., Mambetsariev, N., Flores, C. P. R., Abdala-Valencia, H., Steinert, E. M., Weinberg, S. E., Singer, B. D.. 2025-03-01. Maintenance DNA methylation is required for induced regulatory T cell reparative function following viral pneumonia. https://doi.org/10.1101/2025.02.25.640199

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