Trends Immunol. 2025 Dec 5:S1471-4906(25)00300-X. doi: 10.1016/j.it.2025.11.004. Online ahead of print.
ABSTRACT
The intestinal epithelium functions as an immune-metabolic interface, integrating environmental signals to maintain systemic homeostasis. Intraepithelial lymphocytes (IELs), interspersed within the epithelial layer, form a highly interactive network with intestinal epithelial cells (IECs) to coordinate barrier defense, immune tolerance, and metabolic regulation. IECs orchestrate IEL development, positioning, and functional programming. Reciprocally, IELs modulate epithelial physiology, nutrient uptake, and epithelial repair. Dysregulation of the IEL-IEC unit contributes to intestinal and extraintestinal pathologies. This review discusses current advances in IEL-IEC bidirectional communication, highlighting the influences of diet, microbial metabolites, and immune checkpoints on this interface. We propose a paradigm in which the IEL-IEC interplay functions as a key immunometabolic regulatory unit and represents a promising therapeutic target for systemic diseases.
PMID:41353023 | DOI:10.1016/j.it.2025.11.004