INTERFERON-GAMMA INDUCES A CELL-SURFACE PHENOTYPE SWITCH ON T84 INTESTINAL EPITHELIAL-CELLS

Intestinal epithelia are in intimate contact with submucosal and intra epithelial lymphocytes. The concentration of intraepithelial lymphocyt es increases during inflammatory processes, and, when stimulated, thes e cells generate cytokines such as interferon-gamma (IFN-gamma). In th is study, we examined the effect of recombinant human IFN-gamma on ion transport events in T84 cells, a crypt epithelial cell line widely us ed to study electrogenic Cl- secretion, the transport event responsibl e for mucosal hydration. Epithelial exposure to IFN-gamma brought abou t a marked attenuation in stimulated Cl- secretion, as measured by gen eration of short-circuit current (I-sc) This IFN-gamma-elicited decrea se in the Cl- secretory response was present for a variety of specific agonists, appeared largely due to IFN-gamma interactions with the bas olateral surface, and did not result from a defect in second messenger generation. Efflux and uptake studies were utilized to functionally d efine the individual cell surface transport proteins that participate in Cl- secretion and revealed that, in response to epithelial exposure to IFN-gamma, apical Cl- channels and basolateral Na+-K+-2Cl(-) cotra nsporters, K+ channels, and Na-K-adenosinetriphosphatase were all func tionally downregulated. [H-3]bumetanide binding assays suggested that surface expression of the cotransporter was diminished by >70% after I FN-gamma preexposure. Concurrently, surface immunofluorescence studies revealed that epithelial exposure to IFN-gamma brought about the indu ction of major histocompatibility complex (MHC) class II molecule expr ession on T84 epithelial monolayers and markedly increased MHC class I surface expression. Finally, neutrophilepithelial adhesion studies re vealed that preexposure of epithelial monolayers to IFN-gamma elicited a beta(2)-integrin-dependent induction of neutrophil adhesion. These results suggest a global ''phenotypic switch'' on the intestinal epith elial cell surface from one exhibiting classical epithelial transport function to one expressing significant immune accessory function.