Regulation of Intestinal Epithelial Barrier and Immune Function by Activated T Cells

BACKGROUND & AIMS: Communication between T cells and the intestinal epithelium is altered in many diseases, causing T-cell activation, depletion, or recruitment, and disruption of the epithelium. We hypothesize that activation of T cells regulates epithelial barrier function by targeting the assembly of the tight junction complex. METHODS: In a 3-dimensional and 2-dimensional co-culture model of activated T cells subjacent to the basolateral surface of an epithelial monolayer, the pore, leak, and unrestricted pathways were evaluated using transepithelial resistance and flux of fluorescently labeled tracers. T cells were acutely and chronically activated by cross-linking the T-cell receptor. Tight junction assembly and expression were measured using quantitative polymerase chain reaction, immunoblot, and immunofluorescence confocal microscopy. RESULTS: Co-culture with acutely and chronically activated T cells decreased the magnitude of ion flux through the pore pathway, which was maintained in the presence of acutely activated T cells. Chronically activated T cells after 30 hours induced a precipitous increase in the magnitude of both ion and molecular flux, resulting in an increase in the unrestricted pathway, destruction of microvilli, expansion in cell surface area, and cell death. These fluctuations in permeability were the result of changes in the assembly and expression of tight junction proteins, cell morphology, and viability. Co-culture modulated the expression of immune mediators in the epithelium and T cells. CONCLUSIONS: Bidirectional communication between T cells and epithelium mediates a biphasic response in barrier integrity that is facilitated by the balance between structural proteins partitioning in the mobile lateral phase vs the tight junction complex and cell morphology.