Characterization of epithelial chemoattractants for human intestinal intraepithelial lymphocytes

Abstract

Background & Aims: Although homing of intraepithelial lymphocytes (IEL) into intestinal epithelia seems to be guided by signals from epithelia, little is known concerning functional epithelial-derived chemoattractants for IEL. Methods: Epithelial chemoattractants for IEL were analyzed using chemotaxis chamber system, enzyme-linked immunosorbent assay, and in situ hybridization using human epithelial lines and IEL lines. Results: Epithelial-conditioned media induced IEL chemotaxis, and this activity was markedly enhanced by prestimulation of epithelia with interferon-(IFN)-γ. This chemotaxis (stimulation +) was significantly inhibited by neutralizing antibodies to IFN-γ inducible protein-10 (IP-10) or to monokine induced by IFN-γ (MIG). Furthermore, while high amounts of IP-10 and MIG were detected in epithelial-conditioned media after IFN-γ stimulation, equivalent concentrations of recombinant IP-10 and MIG reproduced IEL chemotaxis. Production of IP-10 and MIG in fresh epithelial cells was supported by in situ hybridization and enzyme-linked immunosorbent assay. Lastly, fresh human IEL constitutively expressed CXCR-3 (the common receptor for IP-10 and MIG), and fresh IEL also exhibited chemotaxis to by rIP-10, rMIG, and epithelial-conditioned media. Conclusions: Epithelial cells produce chemoattractants for IEL, and such chemokine production is regulated by proinflammatory cytokines such as IFN-γ. IP-10 and MIG may serve as potentially important epithelial chemokines for IEL, especially under inflammatory conditions.