LEVELS OF P56(LCK) AND P59(FYN) ARE REDUCED BY A GLUCOCORTICOID-DEPENDENT MECHANISM IN GRAFT-VERSUS-HOST REACTION-INDUCED T-CELL ANERGY

The graft-versus-host reaction (GVHR) results in profound, long-lastin g immunosuppression characterized by T cell unresponsiveness to antige nic and mitogenic stimuli. In this report, the roles of the protein ty rosine kinases p56(lck) and p59(fyn) in GVHR-induced T cell anergy wer e investigated. GVHR was induced by the intravenous transfer of parent al lymphoid cells into Fl hybrid recipient mice. The levels of lck and fyn declined dramatically in splenic and lymph node T cells of mice u ndergoing GVHR as the reaction progressed and T cell immunosuppression developed. Adrenalectomy of the GVH-reactive mice prevented both the GVHR-induced reduction of lck and fyn and the long-term T cell unrespo nsiveness to mitogens, suggesting a glucocorticoid-mediated mechanism. Indeed, treatment with exogenous glucocorticoids induced lck and fyn downregulation in the lymph node T cells of normal mice, and in cultur ed T cell clones. We propose that the increase in endogenous glucocort icoids during GVHR triggers a reduction in T cell Icb: and fyn, leadin g to the severe immunosuppression of GVHR; this may represent a genera l mechanism of glucocorticoid-mediated immune regulation. (C) 1995 Aca demic Press, Inc.