The NF-kappaB regulator Bcl-3 and the BH3-only proteins Bim and Puma control the death of activated T cells

Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10979-84. doi: 10.1073/pnas.0603625103. Epub 2006 Jul 10.

Abstract

Apoptosis of activated T cells is critical for the termination of immune responses. Here we show that adjuvant-stimulated dendritic cells secrete cytokines that prime activated T cells for survival and analyze the roles of the NF-kappaB regulator Bcl-3 and the proapoptotic Bcl-2 family members Bim and Puma. Bcl-3 overexpression increased survival, and activated bcl-3-/- T cells died abnormally rapidly. Cytokines from adjuvant-stimulated dendritic cells induced Bcl-3, but survival through cytokine priming was Bcl-3-independent. Apoptosis inhibition by Bcl-3 involved blockade of Bim activation, because Bim was overactivated in Bcl-3-deficient cells, and Bcl-3 failed to increase survival of bim-/- T cells. However, adjuvants increased survival also in Bim-deficient T cells. This Bim-independent death pathway is at least in part regulated by Puma, as shown by analysis of puma-/- and noxa-/- T cells. IL-1, IL-7, and IL-15 primed T cells for survival even in the absence of Bim or Puma. Our data define interrelations and a Bim-independent pathway to activated T cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic
  • Animals
  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Apoptosis*
  • B-Cell Lymphoma 3 Protein
  • Bcl-2-Like Protein 11
  • Cells, Cultured
  • Dendritic Cells / metabolism
  • Interleukins / pharmacology
  • Lymphocyte Activation
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Solubility
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Transcription Factors
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Adjuvants, Immunologic
  • Apoptosis Regulatory Proteins
  • B-Cell Lymphoma 3 Protein
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Bcl3 protein, mouse
  • Interleukins
  • Membrane Proteins
  • NF-kappa B
  • PUMA protein, mouse
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins