T lymphocyte stress response. I. Induction of heat shock protein synthesis at febrile temperatures is correlated with enhanced resistance to hyperthermic stress but not to heavy metal toxicity or dexamethasone-induced immunosuppression.

Abstract We have investigated the effect of febrile temperatures (≤41 °C) on T cell heat shock protein (hsp) synthesis and the acquisition of stress tolerance. Enhanced synthesis of hsps was detected in highly purified T cells and two cloned T cell lines representing helper T (D10) and cytotoxic T cell (Qa-2 128.38) subsets at temperatures as low as 39 °C with a maximal response at 41 °C. Three major hsps with approximate molecular weights of 110, 90, and 75 were detected in these T cell populations. Western blot analysis using a monoclonal antibody specific for hsp70 indicated that the 75-kDa protein represented hscp70, the cognate or constitutively produced member of the hsp70 family. Although the strongly heat-inducible hsp70 could not be detected in T cells incubated at 41 °C by immunoblot analysis, two-dimensional SDS-PAGE analysis did detect a modest induction of hsp70. Thus, hscp70 and not hsp70 was the major intracellular hsp70 member in T cells incubated at febrile temperatures. Enhanced hsp synthesis reflected augmented transcription of hsp genes which was contingent on the continued presence of hyperthermic stress. In order to determine whether induction of hsp synthesis conferred a state of increased resistance to thermal stress, splenic T cells were incubated at either 37 ° or 41 °C (induction temperatures) and then subjected to a heat-shock challenge temperature. These studies revealed that following heat-shock challenge, mitogen-stimulated T cells preincubated at 41 °C synthesized DNA at an enhanced rate relative to controls (induction temperature, 37 °C). Thus, febrile temperatures were capable of inducing a state of acquired thermotolerance in T cells. However, the thermotolerant state did not protect T cell proliferation against other unrelated stressors such as cadmium and dexamethasone. Reconstitution experiments with accessory cells and interleukin-2-containing supernatants failed to reveal enhanced resistance in thermotolerant T cells to cadmium toxicity or the immunosuppressive activities of dexamethasone. The possibility that higher intracellular concentrations of hsps are required to demonstrate protection against these stressors was tested by the concurrent exposure of T cells to a febrile temperature (41 °C) and ethanol. This resulted in a synergistic increase in hsp90 and hsp70 synthesis; however, there was no evidence of enhanced resistance to cadmium- or dexamethasone-induced stress in T cells given this induction protocol. Similarly, alloreactive cytotoxic T lymphocyte responses were inhibited to the same extent in both control and thermotolerant T cells. Thus, our studies indicate that there is a correlation between induction of hsp synthesis and the acquisition of thermotolerance in T lymphocytes. However, the acquisition of thermotolerance is not associated with increased resistance to stressors such as cadmium or glucocorticoids. The possible role of T cell hsps during a febrile episode and stress are discussed.