The intestine is continuously exposed to diverse microbial, dietary, and environmental signals, requiring tightly regulated immune responses that balance host defense and tolerance. Recent advances in single-cell and multiomic technologies have revealed that immune regulation in barrier tissues cannot be fully explained by circulating immune cells but also by coordinated interactions within local tissue microenvironments. In this review, we introduce a conceptual framework that positions the intestine as a hub of tissue-encoded immune programming. Immune states are established through multilayered systems comprising cellular memory, niche memory, and multicellular circuit stabilization across immune, epithelial, and stromal compartments. These programs are reinforced by epigenetic remodeling, transcription factor networks, and metabolic-epigenetic coupling, enabling long-term adaptation to environmental cues. Within the intestinal microenvironment, specialized antigen-sampling pathways and epithelial barrier programs, together with microbiota-derived cues, actively instruct the localization, differentiation, and functional tuning of tissue-adapted immune populations, including tissue-resident memory T cells (TRM). Importantly, these locally imprinted programs can disseminate systemically and influence immune responses in distal tissues. In inflammatory bowel disease (IBD), these tissue-encoded immune programs become pathologically stabilized, enabling TRM and multicellular circuits to sustain chronic inflammation even in the absence of ongoing triggering signals. This perspective highlights tissue-encoded immune states as central regulators of immunity and disease.
Murakami et al. (Wed,) studied this question.