Levels of p56lck and p59fyn 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-lasting immunosuppression characterized by T cell unresponsiveness to antigenic and mitogenic stimuli. In this report, the roles of the protein tyrosine kinases p56lck and p59fyn in GVHR-induced T cell anergy were investigated. GVHR was induced by the intravenous transfer of parental lymphoid cells into F1 hybrid recipient mice. The levels of lck and fyn declined dramatically in splenic and lymph node T cells of mice undergoing 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 unresponsiveness 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 cultured T cell clones. We propose that the increase in endogenous glucocorticoids during GVHR triggers a reduction in T cell lck and fyn, leading to the severe immunosuppression of GVHR; this may represent a general mechanism of glucocorticoid-mediated immune regulation.