Epigenetic reprogramming of tissue-resident memory T cells in chronic inflammatory disorders and implications for targeted therapies.

BACKGROUND

Tissue-resident memory T (TRM) cells play a role in causing long-term tissue injury in chronic inflammatory diseases via pathological epigenetic reprogramming. Nevertheless, the epigenetic processes that cause this malfunction have not been well defined.

RESEARCH DESIGN AND

METHODS

We performed integrative multi-omics analysis of TRM cells (CD3+CD8+CD69+CD103+, >92% purity, >94% viability) from 124 patients (41 rheumatoid arthritis, 43 inflammatory bowel disease, 40 psoriasis) and 35 healthy controls, employing scATAC-seq, ChIP-seq, whole-genome bisulfite sequencing, and scRNA-seq.

RESULTS

We identified 847 differentially methylated regions (p<0.001) and 1,239 altered chromatin accessibility peaks. Pathogenic programming was sustained through TET2-mediated demethylation of pro-inflammatory enhancers for IL-17A (-43.2% methylation) and TNF (-87.3% methylation). Tissue-specific defects included FOXP3 hypermethylation (+47.3%) in intestinal TRM and elevated H3K27me3 deposition (2.3-fold) in synovial TRM. Combined inhibition using the DNMT1-targeting degrader GSK-3484862 and the EZH2 inhibitor GSK126 reversed pathological programming, reducing cytokine production by >80% in ex vivo assays. Machine learning classification achieved 94.2% accuracy (95% CI: 91.3-97.1%) distinguishing pathogenic from protective TRM cells.

CONCLUSIONS

This first epigenetic atlas of TRM cells in chronic inflammation reveals tissue-specific vulnerabilities, therapeutic targets (DNMT1, EZH2), and patient stratification biomarkers. Limitations include the ex vivo validation system and the need for larger multicentric biomarker validation studies.