Inhibitory effects of transforming growth factor-beta (TGF-beta) on certain functions of intraepithelial lymphocytes.

Human intraepithelial lymphocytes (IEL), CD8+ lymphocytes located between epithelial cells, are likely to be influenced by the immunosuppressive cytokine, TGF-beta, secreted by epithelial cells. This study evaluates the effects of TGF-beta on IEL functions. IEL were derived from proximal jejunum of patients undergoing gastric bypass operations for morbid obesity. Proliferation was determined by 3H-thymidine incorporation; IL-2 production, by ELISA; expression of IL-2 receptor, CD2, HML1, CD16, and CD56, by immunofluorescence; binding, by adherence of radiolabelled cells; and cytotoxicity by 51Cr-release assay. TGF-beta (> or = 1 ng/ml) inhibited the mitosis of IEL to mitogens, IL-7, and stimuli of the CD2 and CD3 pathways. The blocking effect did not target the activation events of IL-2 production and receptor generation. Rather, it reduced cell division after activation when added 24 h after initiating the culture. Antibody neutralization of naturally occurring TGF-beta increased IEL proliferation to IL-2, but not to the other stimuli. Of the multiple surface markers tested, only CD2 and HML1 expression increased with TGF-beta and decreased with antibody to TGF-beta, although the cytokine and the neutralizing antibody had no effects on IEL binding to colon cancer. TGF-beta reduced the number of CD56+ IEL and the lymphokine-activated killing when co-cultured with IL-7 but not with IL-2 or IL-15. TGF-beta inhibits certain IEL functions: the reduction in cell division rather than activation and a decline in IL-7-mediated lysis of colon cancer due to a lowering of the number of natural killer cells.