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Physiological Fever Temperature Induces a Protective Stress Response in T Lymphocytes Mediated by Heat Shock Factor-1 (HSF1)¹

Patience Murapa^*, Siva Gandhapudi^*, Hollie S. Skaggs, Kevin D. Sarge and Jerold G. Woodward^2,*

^* Department of Microbiology, Immunology and Molecular Genetics, and Department of Molecular and Cellular Biochemistry, University of Kentucky Medical Center, Lexington, KY 40536

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°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°C vs 42°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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants EY014060 (to J.G.W.), GM61053 (to K.D.S.), and GM64606 (to K.D.S.). H.S.S. was supported by National Institutes of Health Training Grant T32ES007266.

² Address correspondence and reprint requests to Dr. Jerold G. Woodward, Department of Microbiology, Immunology and Molecular Genetics, MN426, 800 Rose Street, University of Kentucky Medical Center, Lexington, KY 40536. E-mail address: jwood1{at}uky.edu

³ Abbreviations used in this paper: HSF1, heat shock factor-1; DCFH-DA, 2',7'-dichlorodihydrofluorescein diacetate; HSP, heat shock protein; HSP70i, inducible HSP70; ROS, reactive oxygen species.

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