The expression and the regulatory role of OX40 and 4-1BB heterodimer in activated human T cells

Blood. 2005 Sep 15;106(6):2002-10. doi: 10.1182/blood-2004-04-1622. Epub 2005 Jun 7.

Abstract

OX40 and 4-1BB are members of the tumor necrosis factor (TNF) family of costimulatory receptors whose signaling is important for differential immune responses mediated by CD4+ or CD8+ T cells. Although activated T cells may acquire OX40/4-1BB double-positive phenotype and signaling from each receptor is expected to influence cell functions, the relevance between OX40 and 4-1BB has never been investigated before. While we were investigating the expression of OX40 and 4-1BB on activated human T cells, we found that they colocalize. The study of receptor gene-transfected cells showed that both receptors coendocytose and the complex of OX40 and 4-1BB was detected by specific ligands or antibodies (Abs). The heterodimer of OX40 and 4-1BB was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreduced conditions and was associated with the tumor receptor-associated factor (TRAF) family proteins in a unique manner. Furthermore, the stimulation of OX40/4-1BB rendered cells sensitive to apoptosis induced by TNF-alpha that accompanied reduced activation of nuclear factor-kappaB (NF-kappaB). Finally, the OX40/4-1BB stimulation repressed the mitogen response in activated CD25+CD4+ T cells and preactivated CD8+ T cells. Thus, the OX40/4-1BB heterodimer appears to represent a unique regulatory receptor in activated T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / analysis*
  • Antigens, CD / metabolism
  • Antigens, CD / physiology
  • Apoptosis
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Dimerization
  • Endocytosis
  • Humans
  • Lymphocyte Activation*
  • NF-kappa B / metabolism
  • Protein Binding
  • Receptors, Nerve Growth Factor / analysis*
  • Receptors, Nerve Growth Factor / metabolism
  • Receptors, Nerve Growth Factor / physiology
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor / analysis*
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor / physiology
  • T-Lymphocytes / chemistry*
  • T-Lymphocytes / immunology
  • Transfection
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Antigens, CD
  • NF-kappa B
  • Receptors, Nerve Growth Factor
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor
  • TNFRSF4 protein, human
  • TNFRSF9 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Tumor Necrosis Factor-alpha