Regulation of TCR-mediated T cell activation by TNF-RII

J Leukoc Biol. 2003 Oct;74(4):572-82. doi: 10.1189/jlb.0303112. Epub 2003 Jul 1.


In the present study, we investigated the role of tumor necrosis factor receptor II (TNF-RII) in human T cell activation induced via the T cell receptor (TCR) in an antigen-presenting cell-independent system. Our results confirm that interaction of TNF-alpha with TNF-RII but not TNF-RI is directly costimulatory to TCR-mediated T cell activation, thereby augmenting T cell proliferation, expression of T cell activation markers (CD25, human leukocyte antigen-DR, TNF-RII), and secretion of cytokines such as interferon-gamma and TNF-alpha. In contrast to the well-defined costimulatory molecule CD28, costimulation via TNF-RII showed significant differences in kinetics, requirement for cross-linking, redundancy of intracellular signaling pathways involved, and the capacity to induce interleukin (IL)-2, IL-10, and IL-13 secretion. In addition, cross-linking TNF-RII had the capacity to down-regulate TCR/CD28-induced Ca++ mobilization, IL-2 mRNA expression, and IL-2 and IL-10 secretion. Taken together, our findings demonstrate that TNF-RII plays a unique role among the T cell costimulatory molecules, as TNF-RII ligation can have positive and negative effects on TCR-dependent signaling. TNF-RII cross-linking has an inhibitory effect on early TCR signaling events proximal to induction of Ca++ flux, which ultimately leads to modulation of the T cell cytokine pattern expressed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / physiology*
  • CD28 Antigens / physiology
  • Cells, Cultured
  • Humans
  • Interleukin-10 / biosynthesis
  • Interleukin-2 / biosynthesis
  • Lymphocyte Activation*
  • Receptors, Antigen, T-Cell / physiology*
  • Receptors, Tumor Necrosis Factor / physiology*
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Antigens, CD
  • CD28 Antigens
  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • Interleukin-10