Costimulation by CD137/4-1BB inhibits T cell apoptosis and induces Bcl-xL and c-FLIP(short) via phosphatidylinositol 3-kinase and AKT/protein kinase B

Eur J Immunol. 2005 Apr;35(4):1257-66. doi: 10.1002/eji.200425686.

Abstract

Costimulation is essential for induction of T lymphocyte proliferation and inhibition of activation-induced cell death. While signaling pathways activated following the ligation of the costimulatory molecule CD28 are well defined, less is known about the molecular events induced by alternative costimulators. CD137/4-1BB, a costimulatory member of the tumor necrosis factor receptor family, plays an important role during late primary T cell stimulation. Here, we demonstrate for the first time that inhibition of activation-induced cell death by exposure to the CD137/4-1BB ligand involves up-regulation of the anti-apoptotic protein c-FLIP(short). Inhibition of T cell death by 4-1BB ligation and up-regulation of c-FLIP(short) and Bcl-x(L) were abolished by blocking the phosphatidylinositol 3-kinase or the AKT/protein kinase B, which also mediate CD28-induced inhibition of activation-induced cell death. Our findings, therefore, demonstrate that costimulatory molecules, although belonging to different protein families and participating in distinct upstream signaling pathways, employ common downstream signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD
  • Apoptosis / physiology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cell Division / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Receptors, Nerve Growth Factor / metabolism*
  • Receptors, Tumor Necrosis Factor / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / physiology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • bcl-X Protein

Substances

  • Antigens, CD
  • BCL2L1 protein, human
  • Bcl2l1 protein, mouse
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Cflar protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • TNFRSF9 protein, human
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • bcl-X Protein
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt