The long-term goal of our laboratory is to define the role and mechanism of action of glucocorticoids (GCs) in the development of the immune system and the modulation of immune system responses. GCs are among the most potent pharmacologic agents available for the treatment of autoimmune and inflammatory disorders, and deficiency of endogenous GC production dramatically increases the severity of autoimmune, infectious, and inflammatory diseases. Despite these important consequences of excess or inadequate GC action for immune system function, the essential sites and mechanisms by which GCs exert their effects have gone unresolved. In this proposal, we will determine the critical target cell populations upon which endogenous GCs act during immune system development, and the mechanisms by which endogenous and pharmacologically administered GCs impact upon the evolution and treatment of autoimmune/inflammatory disease. We hypothesize that GC actions on the glucocorticoid receptor (GR) within the developing thymocyte and mature T-cell are important components in shaping the T-cell repertoire and limiting the magnitude or duration of immune system activation. To test this hypothesis, we have generated mice capable of conditional inactivation of the GR in developing thymocytes and T-cells (T-GR KO mice). In this proposal, we will analyze the efficiency of positive and negative selection, [and regulation of cytokine production] in T-GR KO mice in vivo, and further evaluate the function of the GR in T-cells during the evolution and treatment of a model autoimmune disease, experimental autoimmune encephalomyelitis (EAE). Based upon the knowledge gained, novel and improved interventions for human disease, that separate therapeutic and harmful consequences of GC action, will be elucidated.
