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: 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: validation system and the need for larger multicentric biomarker validation studies.