DISRUPTION OF HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN TRANSGENIC MICE EXPRESSING TYPE-II GLUCOCORTICOID RECEPTOR ANTISENSE RIBONUCLEIC-ACID PERMANENTLY IMPAIRS T-CELL FUNCTION - EFFECTS ON T-CELL TRAFFICKING AND T-CELL RESPONSIVENESS DURING POSTNATAL-DEVELOPMENT

We used transgenic mice with impaired corticosteroid receptor function, caused by expression of type II glucocorticoid receptor (GR) antisense RNA, to study the role of glucocorticoid feedback during the developmental maturation of hypothalamus-pituitary-adrenal-immune functions. These mice have increased plasma concentrations of ACTH and corticosterone as well as reduced GR binding capacity. In control mice, a strong sex dimorphism in the development of GR gene expression is apparent, and in males between postnatal days 9-36, the GR gene transcript concentration is approximately twice that in female mice. Endogenous GR messenger RNA levels were markedly reduced in transgenic mice, and the sex dimorphism was abolished. An abnormal developmental pattern of adrenal secretory activity accompanied the postnatal maturation of the hypothalamic-pituitary-adrenocortical system of the transgenic mice, and high plasma corticosterone levels were measured at early postnatal ages through adulthood. Inefficient glucocorticoid inhibitory action on the immune axis was supported by both the inability of high circulating levels of corticosterone to reduce thymus weight and the failure of dexamethasone to influence in vitro thymocyte and splenocyte cell proliferation. Alterations in thymocyte trafficking/migration in transgenic mice was supported by flow cytometric analysis of the distribution of phenotypically distinct lymphocyte subsets accompanying the postnatal maturation of the thymus. A marked increase in CD4(+)CD8(+) double positive cells and a 2-fold increase in the CD4/CD8 (helper/suppressor) ratio caused by a 40-60% increase in the CD4(+)CD8(-) (T helper) subset and a decrease in the CD4(-)CD8(+) (T suppressor) subset, was seen. Moreover, in transgenic mice, an absence of sexual dimorphism and a significantly increased immune reactivity were observed. The present study shows that disruption of the hypothalamic-pituitary-adrenocortical system has both developmental and permanent effects on T cell function characterized by a shifting of the T cell balance toward the CD4(+)CD8(-) helper-inducer phenotype coupled with hyperresponsiveness of the T (helper) cell compartment. These findings point to the GR as a major factor in the counterregulatory feedback loop controlling autoaggressive immune responses and underline the potential modulatory role of sex steroids in this feedback regulation and in the pathogenesis of autoimmune diseases.