T cell anergy has been correlated with defective signaling by the GTPase Ras, but causal and mechanistic data linking defective Ras activity with T cell anergy are lacking. Here we used adenoviral transduction to genetically manipulate nonproliferating T cells and show that active Ras restored interleukin 2 production and mitogen-activated protein kinase signaling in T cells that were made anergic in vitro or in vivo. Diacylglycerol kinases (DGKs), which negatively regulate Ras activity, were upregulated in anergic T cells, and a DGK inhibitor restored interleukin 2 production in anergic T cells. Both anergy and DGK-alpha overexpression were associated with defective translocation of the Ras guanine nucleotide-exchange factor RasGRP1 to the plasma membrane. Our data support a causal function for excess DGK activity and defective Ras signaling in T cell anergy.
Golden shiners (Notemigonus crysoleucas) require a dietary source of ascorbic acid (AA) for growth or survival, depending on diet composition. However, no quantitative requirements of golden shiners for AA for growth, health or survival have been determined, and specific deficiency signs have not been observed. The purpose of this study was to determine the effects of different dietary levels of AA on the growth and health of golden shiners fed diets containing 0-218.5 mg AA/kg diet for 10-16 wk. Weight gain, survival and gross deformities were assessed at 10 wk. The remaining fish were fed the same diets from wk 11-16; hematology and alternative complement activity were then assessed and a subset of live fish from each tank was exposed to elevated temperature. Gross deformities appeared in fish fed 0 mg AA/kg diet at 9 wk. The 19.5 mg AA/kg diet was sufficient to prevent the deformities and optimize survival, whereas growth did not differ among treatments. Fish fed 40.3 mg of AA/kg diet had a higher survival rate than fish fed 0 or 19.5 mg AA/kg diet after exposure to elevated temperatures (34-35.5 degrees C). Alternative complement activity and visceral AA concentrations were greater in fish fed diets with 218.5 mg AA/kg than in all other groups. The results indicate that the dietary requirement of AA for golden shiners increases in response to heat stress, and that the alternative complement activity (one index of immune competence) was strongly enhanced in fish fed a diet with approximately 10 times the amount of AA required to prevent deficiency signs.
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