Activation of c-jun N-terminal kinase by 4-1BB (CD137), a T cell co-stimulatory molecule

Mol Cells. 2000 Jun 30;10(3):247-52.


It has been widely accepted that T cell activation requires two signals; one from the binding of the antigen/major histocompatibility complex to the T-cell receptor (TCR)/CD3 complex and the other from the interaction between a surface molecule on antigen presenting cells and its receptor on T cells. The second signal is considered as co-stimulatory and the B7/CD28 pair has been well studied as a prototype. Recently 4-1BB (CD137) has been characterized as another co-stimulatory molecule for T cell activation. However, unlike the CD28/B7 pair, 4-1BB and its ligand 4-1BBL constitute a member of the tumor necrosis factor (TNF) receptor/TNF pair superfamily. The signaling mechanism of 4-1BB has not been revealed in detail. To investigate whether 4-1BB takes the signaling pathways analogous to those for TNF receptors, we generated polyclonal antibodies against human 4-1BB and 4-1BBL and established stable transfectants of the receptor and the ligand with a high level of cell surface expression. Over-expression of h4-1BB was found to result in the activation of c-Jun N-terminal kinase (JNK) in the human embryonic kidney cell line 293. In T cells, it has been previously demonstrated that JNK activation requires dual signals such as the ligation of TCR/CD3 complex plus CD28 co-stimulation or PMA plus ionomycin. The JNK activation by 4-1BB in Jurkat T cells was also found to require stimulation of the TCR/CD3 complex, consistent with the notion that 4-1BB functions as a co-stimulatory molecule for T cell activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand
  • Animals
  • Antibodies / isolation & purification
  • Antigens, CD
  • Blotting, Western
  • Cell Extracts
  • Cell Line
  • Enzyme Activation
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Jurkat Cells
  • Ligands
  • Lymphocyte Activation
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Plasmids
  • Rabbits
  • Receptors, Nerve Growth Factor / immunology
  • Receptors, Nerve Growth Factor / metabolism*
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology
  • Transfection
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor-alpha / immunology


  • 4-1BB Ligand
  • Antibodies
  • Antigens, CD
  • Cell Extracts
  • Ligands
  • Membrane Glycoproteins
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • TNFRSF9 protein, human
  • TNFSF9 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor-alpha
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases