Physiological fever temperature induces a protective stress response in T lymphocytes mediated by heat shock factor-1 (HSF1).
Heat shock factor-1 (HSF1) is a transcription factor that serves as the major temperature-inducible sensor for eukaryotic cells. In most cell types, HSF1 becomes activated to the DNA binding form at 42 degrees C and mediates the classical heat shock response, protecting the cells from subsequent lethal temperatures. We have recently demonstrated that HSF1 is activated at a lower temperature in T lymphocytes than in most other cell types (39 degrees C vs 42 degrees C), within the physiological range of fever. In this study, we show that T cell activation at fever temperatures not only activates HSF1 but induces the up-regulation of the HSF1 protein and the HSF1-regulated protein, HSP70i. T cells from HSF1 knockout mice proliferate normally under optimal conditions but are impaired in proliferation at physiological fever temperatures and low CO2 concentrations, conditions that do not impair wild-type T cells. This defect in proliferation appears to be mediated by a block in the G1/S transition of the cell cycle and is independent of HSP70. Elevated temperature and low CO2 concentrations resulted in a dramatic reduction of the intracellular reactive oxygen species (ROS) levels in both normal and knockout T cells. Wild-type T cells were able to restore ROS levels to normal within 5 h, whereas HSF1-/- T cells were not. These results suggest that the proliferation defect seen in T cells from HSF1-/- mice at fever temperatures was because of dysregulated ROS levels and that HSF1 is important in maintaining ROS homeostasis and cell cycle progression under the stressful conditions encountered during fever.
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky Medical Center, Lexington 40536, USA.
Patience
P
Murapa
Siva
S
Gandhapudi
Hollie S
HS
Skaggs
Kevin D
KD
Sarge
Jerold G
JG
Woodward
D000818:Animals; D001831:Body Temperature / Q000276:immunology*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005334:Fever / Q000276:immunology*; D016193:G1 Phase / Q000235:genetics / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D016196:S Phase / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors