Unveiling the guardians: IL-26-expressing MAIT cells protect epithelial barrier function and are dysregulated in Crohn's disease

BACKGROUND & AIMS Inflammatory bowel disease (IBD) is characterized by a dysregulated immune response against the host’s microbiome. Mucosal-associated invariant T (MAIT) cells recognize microbiota-derived riboflavin metabolites and play a crucial role in mucosal homeostasis. However, their specific role in IBD remains enigmatic. MAIT cells express IL-26, a novel IL-10 family cytokine with a controversial role in IBD. We investigated the functions of MAIT cells and IL-26 in IBD using a unique combination of state-of-the-art 3D human intestinal tissue models and clinical samples. METHODS We analyzed MAIT cells from the peripheral blood and intestinal tissue of Crohn’s disease (CD) patients, using immunofluorescence staining and flow cytometry to describe the phenotype and IL-26 expression of MAIT cells. We used 3D iPSC-derived intestinal organoids as a complex in vitro model of human tissue and RNA sequencing and functional assays such as wound healing assay to study the role of IL-26 in mucosal homeostasis and inflammation. RESULTS We observed a reduction of MAIT cells in the peripheral blood of CD patients compared to healthy donors (1.5 ± 0.4%; 4.1 ± 1.1%; p < .0065) and a significant decrease of MAIT cells in inflamed compared to non-inflamed ileum of CD patients (0.1 ± 0.03%; 0.17 ± 0.05%; p < .042). MAIT cells were found pathologically activated in inflamed tissue, exhibiting differences in CD8 and CD4 expression and dysregulation of IL-26 expression. Furthermore, we demonstrated a protective role of IL-26 in mucosal homeostasis and inflammation in the iPSC-derived organoid model. CONCLUSION Our results show a crucial role for IL-26 and MAIT cells in the homeostasis of intestinal tissue and in the pathogenesis of IBD. These cells may therefore represent new therapeutic targets for CD patients.