T cell selective apoptosis by a novel immunosuppressant, FTY720, is closely regulated with Bcl-2.

1. A novel immunosuppressant FTY720 caused a significant decrease in peripheral T lymphocytes, but not in B lymphocytes upon oral administration. This decrease was mainly a result of FTY720-induced apoptosis. In this study, we confirmed FTY720-induced T cell selective apoptosis using lymphoma cell lines in vitro. 2. Viability loss, DNA fragmentation, Annexin V binding, and caspases activation (caspase-3, -8, and -9) were observed in Jurkat cells (T lymphoma cells), but not significantly in BALL-1 cells (B lymphoma cells). These results indicated that FTY720 selectively induced apoptosis in T cell lymphoma to a greater extent than in B cell lymphoma, a finding that is similar to the result observed when FTY720 was treated with T lymphocytes and B lymphocytes in vitro. 3. FTY720 released cytochrome c from mitochondria in Jurkat intact cells as well as from isolated Jurkat mitochondria directly, but not from mitochondria in BALL-1 cells nor from isolated BALL-1 mitochondria. 4. BALL-1 cells and B cells had more abundant mitochondria-localized anti-apoptotic protein Bcl-2 than did Jurkat cells and T cells. 5. FTY720-induced apoptosis is inhibited by the overexpression of Bcl-2, suggesting that the cellular Bcl-2 level regulates the sensitivity to FTY720.