Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses

Eur J Immunol. 1998 Mar;28(3):881-90. doi: 10.1002/(SICI)1521-4141(199803)28:03<881::AID-IMMU881>3.0.CO;2-0.


Our present study provides evidence that the 4-1BB signal is critical to CD28 co-stimulation in maintaining T cell activation when CD28 has been down-regulated because of repeated stimulation. The 4-1BB signal synergized with CD28 co-stimulation by lowering the threshold of anti-CD28 required to sustain proliferation and IL-2 production. The 4-1BB signal also modulated CD28-mediated cytokine profiles by markedly enhancing Th1 but suppressing Th2-type cytokine production. The 4-1BB signal generated Th1-type cells, as identified by intracellular IFN-gamma production. IFN-gamma induction was detected preferentially in 4-1BB-expressing cells, but not in those expressing CD30. 4-1BB and CD30 were induced in both CD4+ and CD8+ cells, but the location of the two molecules was mutually exclusive in each T cell subset. Our study suggests that the 4-1BB signal regulates CD28 co-stimulation in the targeted subset cells to favor Th1 development and maintain long-term cell growth.

Publication types

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

MeSH terms

  • Antigens, CD
  • CD28 Antigens / physiology*
  • Cell Division
  • Cytokines / biosynthesis
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-4 / biosynthesis
  • Ki-1 Antigen / analysis
  • Lymphocyte Activation
  • Receptors, Nerve Growth Factor / physiology*
  • Receptors, Tumor Necrosis Factor / physiology*
  • S Phase
  • Signal Transduction
  • T-Lymphocyte Subsets / physiology*
  • Th1 Cells / physiology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9


  • Antigens, CD
  • CD28 Antigens
  • Cytokines
  • Ki-1 Antigen
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • TNFRSF9 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Interleukin-4
  • Interferon-gamma