Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes

Immunity. 1999 Dec;11(6):763-70. doi: 10.1016/s1074-7613(00)80150-8.

Abstract

The induction of apoptosis by death receptors serves to regulate immune responses by eliminating unwanted and harmful cells. Mature lymphocytes express FLICE inhibitory proteins (FLIPs) that block death receptor-induced cell death. Here, we show that both B and T cells downregulate c-FLIP upon activation in vitro. Retrovirus-mediated expression of c-FLIP blocks Fas-induced apoptosis of activated lymphocytes but does not affect cell death resulting from cytokine withdrawal. In vivo, c-FLIP expression results in defective superantigen-mediated elimination of T cells, the accumulation of activated B cells, the production of autoantibodies, and the development of autoimmune disease. No effect was seen on negative selection of thyomocytes. These results suggest that activation-dependent downregulation of c-FLIP renders mature lymphocytes sensitive to death receptor-mediated apoptosis and is required to maintain self-tolerance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Retracted Publication

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Apoptosis
  • Autoimmune Diseases / immunology
  • Autoimmunity / immunology*
  • B-Lymphocytes / immunology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Cells, Cultured
  • Down-Regulation
  • Enterotoxins / immunology
  • Fas-Associated Death Domain Protein
  • Gene Expression
  • Genetic Vectors / genetics
  • Intracellular Signaling Peptides and Proteins*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Ovalbumin / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Retroviridae / genetics
  • Staphylococcus aureus / immunology
  • Superantigens / immunology
  • T-Lymphocytes / immunology*
  • fas Receptor / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins
  • Cflar protein, mouse
  • Enterotoxins
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Intracellular Signaling Peptides and Proteins
  • Recombinant Fusion Proteins
  • Superantigens
  • fas Receptor
  • trinitrophenyl-ovalbumin
  • enterotoxin B, staphylococcal
  • Ovalbumin