The Trm-Treg Axis as a tissue-encoded immune checkpoint in chronic inflammation and autoimmunity.

Tissue-resident memory T (Trm) cells, once heralded as gatekeepers of localized immune protection, have emerged as central players in the pathogenesis of chronic inflammation and autoimmunity at epithelial barriers. At the heart of this immunological paradox lies the dynamic interplay between Trm and regulatory T (Treg) cells-a tissue-encoded checkpoint that calibrates immune defense against the need for tolerance and repair. Disruption of this axis unleashes the latent pathogenicity of Trm cells, fueling persistent inflammation, epithelial dysfunction, and disease relapse. Here, we propose that the Trm-Treg interaction acts as a molecular rheostat that tunes immune homeostasis at barrier sites. We dissect the tissue-specific mechanisms that sustain this alliance, highlight its failure in diseases such as inflammatory bowel disease (IBD), psoriasis, and chronic obstructive pulmonary disease (COPD), and explore emerging therapeutic strategies aimed at recalibrating this immune checkpoint to restore durable epithelial tolerance.