Co-stimulation of antigen-specific CD4 T cells by 4-1BB ligand

Eur J Immunol. 2000 Feb;30(2):392-402. doi: 10.1002/1521-4141(200002)30:2<392::AID-IMMU392>3.0.CO;2-H.


4-1BB is a member of the TNF receptor family predominantly expressed on activated T cells, and binds an inducible ligand found on B cells, macrophages and dendritic cells. Whereas ligation of 4-1BB has been shown to enhance response of purified CD8 T cells to mitogens, and to augment NK activity and generation of cytotoxic T lymphocytes in vivo, there are little direct data on 4-1BB action during CD4 responses. Using pigeon cytochrome c-presenting fibroblast antigen-presenting cells transfected with 4-1BB ligand (4-1BBL), we show that engaging 4-1BB on naive CD4 cells promotes proliferation, cell cycle progression and IL-2 secretion, and suppresses cell death, all to a similar extent as B7-1 engagement of CD28. In addition, 4-1BBL synergizes with B7 and ICAM to enhance naive CD4 proliferation when antigen is limiting. 4-1BBL alone, and to a greater extent with B7, also augmented IL-2 secretion resting antigen-experienced CD4 cells, as typified by T helper clones, whereas short-term effector cells showed similar levels of proliferation and cytokine secretion regardless of whether 4-1BB was engaged. A major role in augmenting IFN-gamma, IL-4 or IL-5 was not demonstrated. Blocking studies with activated B cells presenting antigen showed that 4-1BB participates in promoting IL-2 production by resting CD4 cells, confirming that 4-1BBL can play a role in antigen-specific CD4 T cell responses.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-1BB Ligand
  • Animals
  • Antigen Presentation
  • Cells, Cultured
  • Ligands
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Transgenic
  • T-Lymphocytes / immunology*
  • Tumor Necrosis Factor-alpha / immunology*


  • 4-1BB Ligand
  • Ligands
  • Tnfsf9 protein, mouse
  • Tumor Necrosis Factor-alpha