Regulation of 4-1BB expression by cell-cell interactions and the cytokines, interleukin-2 and interleukin-4

Eur J Immunol. 1995 Feb;25(2):488-94. doi: 10.1002/eji.1830250227.


4-1BB expression increased gradually following T cell activation, and by day 3 post-stimulation with immobilized anti-CD3 (anti-CD3i) or concanavalin A (Con A), splenic T cells were routinely 35-45% 4-1BB+ by flow cytometric analysis. 4-1BB was expressed on activated CD8+, CD4+, CD28+ and CD45RB+ T cells. Optimal 4-1BB expression was seen by day 6 post-stimulation and was cell density dependent. When T cells were cultured for 6 days at 1 x 10(6)/well in a 24-well plate with anti-CD3i, 82% of the cells were 4-1BB+. In contrast, at lower cell densities (4 x 10(5), 2 x 10(5) and 1 x 10(5)), optimal 4-1BB expression was observed only if the cultures were supplemented with recombinant interleukin-2 (IL-2) or recombinant IL-4 (IL-4). In agreement, with these results, modes of inducing endogenous IL-2 production such as cross-linking the costimulatory molecule, CD28, or the addition of syngeneic accessory cells to T cells activated with anti-CD3i, resulted in high levels of 4-1BB expression. The addition of interleukin-1 alpha (IL-1 alpha) or interferon-gamma (IFN-gamma) did not increase 4-1BB expression on anti-CD3i-activated T cells. In addition, if T cells were incubated with IL-2, IL-4, IL-1 alpha, IFN-gamma or anti-CD28 alone, no 4-1BB expression was induced. T cells activated with soluble anti-CD3 (anti-CD3s) in the presence of IL-2, IL-4, or accessory cells, did not express higher levels of 4-1BB on their cell surface. These data suggest that initial events crucial for efficient T cell activation, such as signals delivered through the T cell receptor/CD3 complex and the CD28 molecule, are instrumental in regulating subsequent 4-1BB expression.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD
  • CD28 Antigens / physiology
  • CD3 Complex / immunology
  • Cell Communication*
  • Female
  • Interferon-gamma / pharmacology
  • Interleukin-1 / pharmacology
  • Interleukin-2 / pharmacology*
  • Interleukin-4 / pharmacology*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Nerve Growth Factor / analysis*
  • Receptors, Tumor Necrosis Factor / analysis*
  • T-Lymphocytes / chemistry*
  • T-Lymphocytes / physiology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9


  • Antigens, CD
  • CD28 Antigens
  • CD3 Complex
  • Interleukin-1
  • Interleukin-2
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Interleukin-4
  • Interferon-gamma