Fever-like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

J Immunol. 2007 Mar 15;178(6):3944-53. doi: 10.4049/jimmunol.178.6.3944.

Abstract

Fever has a major impact on immune responses by modulating survival, proliferation, and endurance of lymphocytes. Lymphocyte persistence in turn is determined by the equilibrium between death and survival-promoting factors that regulate death receptor signaling in these cells. A potential integrator of death receptor signaling is the caspase-8 inhibitor c-FLIP, the expression of which is dynamically regulated, either rapidly induced or down-regulated. In this study, we show in activated primary human T lymphocytes that hyperthermia corresponding to fever triggered down-regulation of both c-FLIP-splicing variants, c-FLIPshort (c-FLIP(S)) and c-FLIPlong, with consequent sensitization to apoptosis mediated by CD95 (Fas/APO-1). The c-FLIP down-regulation and subsequent sensitization was specific for hyperthermic stress. Additionally, we show that the hyperthermia-mediated down-regulation was due to increased ubiquitination and proteasomal degradation of c-FLIP(S), the stability of which we have shown to be regulated by its C-terminal splicing tail. Furthermore, the induced sensitivity to CD95 ligation was independent of heat shock protein 70, as thermotolerant cells, expressing substantially elevated levels of heat shock protein 70, were not rescued from the effect of hyperthermia-mediated c-FLIP down-regulation. Our findings indicate that fever significantly influences the rate of lymphocyte elimination through depletion of c-FLIP(S). Such a general regulatory mechanism for lymphocyte removal has broad ramifications for fever-mediated regulation of immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / immunology
  • Apoptosis* / immunology
  • CASP8 and FADD-Like Apoptosis Regulating Protein / immunology
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Caspase 8 / metabolism
  • Caspase Inhibitors
  • Down-Regulation
  • Fever / immunology
  • Fever / metabolism*
  • Fever / pathology
  • HSP70 Heat-Shock Proteins / biosynthesis
  • HSP70 Heat-Shock Proteins / immunology
  • Heat-Shock Response* / immunology
  • Humans
  • Jurkat Cells
  • Protease Inhibitors / immunology
  • Protease Inhibitors / metabolism*
  • Proteasome Endopeptidase Complex / immunology
  • Proteasome Endopeptidase Complex / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology
  • Ubiquitin / immunology
  • Ubiquitin / metabolism
  • fas Receptor / immunology
  • fas Receptor / metabolism

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Caspase Inhibitors
  • HSP70 Heat-Shock Proteins
  • Protease Inhibitors
  • Ubiquitin
  • fas Receptor
  • CASP8 protein, human
  • Caspase 8
  • Proteasome Endopeptidase Complex