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.