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

Eur J Immunol. 2001 May;31(5):1410-6. doi: 10.1002/1521-4141(200105)31:5<1410::AID-IMMU1410>3.0.CO;2-H.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antigens, CD
  • Apoptosis* / drug effects
  • B7-1 Antigen / genetics
  • B7-1 Antigen / metabolism
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cytotoxicity, Immunologic
  • Fas Ligand Protein
  • Female
  • Macrolides*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / metabolism*
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Transcription, Genetic / drug effects
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation / drug effects

Substances

  • 4-1BB Ligand
  • Anti-Bacterial Agents
  • Antigens, CD
  • B7-1 Antigen
  • Caspase Inhibitors
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Macrolides
  • Membrane Glycoproteins
  • RNA, Messenger
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf9 protein, mouse
  • Tnfsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor-alpha
  • concanamycin A
  • Caspases