TY - JOUR
T1 - Fever-like hyperthermia controls T Lymphocyte persistence by inducing degradation of cellular FLIPshort
AU - Meinander, Annika
AU - Söderström, Thomas S
AU - Kaunisto, Aura
AU - Poukkula, Minna
AU - Sistonen, Lea
AU - Eriksson, John E
PY - 2007/3/15
Y1 - 2007/3/15
N2 - 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.
AB - 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.
KW - Alternative Splicing/immunology
KW - Apoptosis/immunology
KW - CASP8 and FADD-Like Apoptosis Regulating Protein/immunology
KW - Caspase 8/metabolism
KW - Caspase Inhibitors
KW - Down-Regulation
KW - Fever/immunology
KW - HSP70 Heat-Shock Proteins/biosynthesis
KW - Heat-Shock Response/immunology
KW - Humans
KW - Jurkat Cells
KW - Protease Inhibitors/immunology
KW - Proteasome Endopeptidase Complex/immunology
KW - T-Lymphocytes/immunology
KW - Ubiquitin/immunology
KW - fas Receptor/immunology
U2 - 10.4049/jimmunol.178.6.3944
DO - 10.4049/jimmunol.178.6.3944
M3 - Article
C2 - 17339495
SN - 0022-1767
VL - 178
SP - 3944
EP - 3953
JO - Journal of Immunology
JF - Journal of Immunology
IS - 6
ER -