The contribution of genetics to the development of gut-related autoimmune diseases such as celiac disease (CeD) and inflammatory bowel diseases (IBDs) is well-established, especially in immune cells, but pinpointing the significance of genetic variants to other cell types is more elusive. Increasing evidence indicates that intestinal epithelial cells are active players in modulating the immune response, suggesting that genetic variants affecting these cells could change cell behavior during disease. Moreover, fine-mapping genetic variants and causal genes to relevant cell types can help to identify drug targets and develop personalized targeted therapies. In this context, we reviewed the functions of genes in disease-associated loci shared by CeD and IBD that are expressed in epithelial cells and explored their potential impacts.

Interactions between intraepithelial lymphocytes (IELs) and the intestinal epithelium are central to mucosal homeostasis and disease. However, mechanistic in vitro studies describing their crosstalk in humans are limited by scarceness of primary material and insufficient knowledge about co-culture requirements. Here, we establish an autologous human duodenal IEL–organoid co-culture system encompassing expandable and bankable IEL and organoid protocols, with co-culture conditions that allow viability of both cell types. This system enables successive interrogation of lympho-epithelial interactions starting from minimal biopsy material. Under baseline conditions, CD45⁺CD8⁺CD103⁺TCRαβ⁺ IELs retain tissue-residency and effector features and induce an epithelial interferon response and chemokine production, without overt epithelial apoptosis. IL-15 and IL-21, essential cytokines involved in IEL-activation in intestinal enteropathies like celiac disease, increases granzyme B expression and interferon-γ secretion but do not trigger epithelial cell death. However, enforcing IEL-epithelial contact using an anti-CD3-anti-Ep-CAM bispecific antibody induces epithelial apoptosis accompanied by increased tumor necrosis factor (TNF) and FAS-ligand (FASLG) secretion. These findings validate the platform’s ability to resolve non-destructive and cytotoxic lympho-epithelial interaction and provide a tractable system for studying intestinal inflammation and immune-mediated epithelial cell death.