Objective. To examine the effects of nitric oxide (NO) and its more stable derivative, S-nitrosoglutathione (SNO-GSH), on the response of activated T lymphocytes.Methods. The effects of NO and SNO-GSH on DNA synthesis, interleukin-2 (IL-2) production, IL-2 receptor expression, and cGMP accumulation were determined in phytohemagglutinin-activated peripheral blood mononuclear cells (PBMC) and spleen T cells. Results. Nitric oxide (half-life [T,,,] < 15 seconds)did not inhibit T cell proliferation. However, the derivative SNO-GSH (25 ErM) (TI,, >2 hours) inhibited DNA synthesis by a mean 2 SD of 65 2 19.6% (P < 0.001) in PBMC and 75 f 15% (P < 0.001) in spleen cells.Macrophage depletion of PBMC did not abrogate the inhibition. SNO-GSH had no effect on IL-2 production or IL-2 receptor expression. NO (25 ptf) increased the cGMP content of PBMC (0.65 f 0.15 pmoles/106 cells; P < 0.04), as did SNO-GSH (25 ptf) in both PBMC (3.8 2 1; P < 0.001) and spleen T cells (5.2 f 1.2; P < 0.001). Methylene blue and hemoglobin, which are NO inhibitors, inhibited SNO-GSH-induced cGMP accumulation (P < 0.001).Conclusion. SNO-GSH inhibits T cell DNA synthesis independently of IL-2 production and in associa-