Rapid induction of CD95 ligand and CD4(+) T cell-mediated apoptosis by CD137 (4-1BB) costimulation

We investigated the cytolytic mechanism by CD4(+) T cells in anti-CD3 mAb-i nduced redirected cytotoxicity against a murine Pc receptor-bearing mastocy toma (P815) transfected with either CD80 or CD137 ligand (CD137L). CD137 co stimulation preferentially induced anti-CD3-induced redirected cytotoxicity within 4 h. This cytotoxicity was efficiently abrogated by the addition of anti-CD137L or anti-CD95L mAb, or by treatment with a broad caspase inhibi tor, Z-VAD, suggesting that the induced cytotoxicity against CD137L-P815 is dependent on CD95L-mediated apoptosis. In contrast, the cytotoxicity again st CD80-P815, but not CD137L-P815 was efficiently inhibited by an inhibitor of perforin-dependent cytotoxicity, concanamycin A. Involvement of CD95L i n the CD137L-dependent cytotoxicity was confirmed by a failure of induction of cytotoxicity by CD4(+) T cells from CD95L-gene mutated gld mice. A rapi d and remarkable induction of CD95L transcription within 1 h was observed b y CD137L costimulation. These results demonstrated that CD137L costimulatio n induces a rapid induction of CD95L on CD4(+) T cells and leads to apoptos is of CD95-sensitive target cells. This biological function of CD137 in CD4 (+) T cells may play an important role for immune homeostasis.