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-induced redirected cytotoxicity against a murine Fc receptor-bearing mastocytoma (P815) transfected with either CD80 or CD137 ligand (CD137L). CD137 costimulation 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 inhibitor, Z-VAD, suggesting that the induced cytotoxicity against CD137L-P815 is dependent on CD95L-mediated apoptosis. In contrast, the cytotoxicity against CD80-P815, but not CD137L-P815 was efficiently inhibited by an inhibitor of perforin-dependent cytotoxicity, concanamycin A. Involvement of CD95L in the CD137L-dependent cytotoxicity was confirmed by a failure of induction of cytotoxicity by CD4+ T cells from CD95L-gene mutated gid mice. A rapid and remarkable induction of CD95L transcription within 1 h was observed by CD137L costimulation. These results demonstrated that CD137L costimulation induces a rapid induction of CD95L on CD4+ T cells and leads to apoptosis of CD95-sensitive target cells. This biological function of CD137 in CD4+ T cells may play an important role for immune homeostasis.