Mucosa-associated invariant T (MAIT) cells are a prominent subset of innate-like T cells enriched in epithelial barrier tissues, where they contribute to frontline defense against bacterial pathogens. In the human gastrointestinal (GI) tract, MAIT cells display features of tissue-resident memory T (TRM) cells, yet their recruitment dynamics, effector functions, and tissue adaptation, and retention remain poorly defined in human settings.
To address this, we established a three-dimensional (3D) human intestinal organoid platform to model MAIT cell behaviour under tissue-relevant conditions. MAIT cells represent a previously underappreciated but abundant population of antibacterial TRM cells in the human gut, uniquely positioned to respond rapidly to bacterial invasion. Co-culture of gut-derived organoids with Escherichia coli and circulating MAIT cells revealed robust MAIT cell recruitment, characterised by chemokine-driven migration, cytokine production, cytotoxic responses, and acquisition of TRM markers. Interaction between MAIT cells and gut organoids was sufficient to generate TRM-like MAIT cells in vitro, suggesting the capacity of the organoid environment to provide the necessary tissue-derived cues for tissue residency programming.
To extend these observations under inflammatory conditions, we incorporated organoids derived from tissues of patients with appendicitis, capturing the chemokine and cytokine milieu of acute intestinal inflammation. These models supported and validated MAIT cell recruitment and effector activation in a disease-relevant context, while reinforcing the versatility of the system to mimic various infectious and inflammatory gut environments.
Altogether, these findings suggest that MAIT cell–organoid interactions reflect key aspects of MAIT cell antimicrobial function and tissue adaptation. This system provides a useful model for investigating MAIT cell–epithelial interactions in human intestinal tissues under both homeostatic and inflammatory conditions. It may help clarify the roles of MAIT cells in mucosal immunity and their contributions to gut immune regulation and microbial control.