TGF-beta mediates natural suppressor activity of IL-2-activated lymphocytes

In addition to generating cells with non-MHC-restricted cytotoxic activity that is characteristic of lymphokine-activated killer (LAK) cells, in vitro cultures of lymphocytes with relatively high concentrations of IL-2 generate cells that simultaneously exhibit two distinct types of suppressor activities: veto, the ability of cells to specifically suppress generation of allo-CTL against their own histocompatibility Ags; and natural suppression, the ability of these same cells to nonspecifically suppress the generation of allo-CTL against both their own and unrelated cell surface Ags. In contrast to veto, which is known to require cell-cell contact between veto-active cells and precursors of CTL, natural suppression is known to be mediated by soluble factors. To identify and characterize suppressor factors that might mediate the natural suppressor activity of IL-2-activated lymphocytes, murine spleen cells were cultured with 1000 U/ml IL-2, and, after varying periods of incubation, their LAK cytolytic activity and natural suppressor activity was determined and cell supernatants were collected and tested for their effects on mixed lymphocyte culture-induced generation of allo-CTL. Like the IL-2-activated lymphocytes themselves, supernatants of these cells nonspecifically inhibited mixed lymphocyte culture-induced generation of allo-CTL. Rabbit anti-TGF-beta specifically neutralized the suppressive effects of both LAK cell supernatants and the IL-2-activated lymphocytes themselves. These findings indicate that TGF-beta is the primary mediator of the natural suppressor activity of IL-2-activated lymphocytes.