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) antisen se RNA, to study the role of glucocorticoid feedback during the develo pmental maturation of hypothalamus-pituitary-adrenal-immune functions. These mice have increased plasma concentrations of ACTH and corticost erone as well as reduced GR binding capacity. In control mice, a stron g sex dimorphism in the development of GR gene expression is apparent, and in males between postnatal days 9-36, the GR gene transcript conc entration is approximately twice that in female mice. Endogenous GR me ssenger RNA levels were markedly reduced in transgenic mice, and the s ex dimorphism was abolished. An abnormal developmental pattern of adre nal secretory activity accompanied the postnatal maturation of the hyp othalamic-pituitary-adrenocortical system of the transgenic mice, and high plasma corticosterone levels were measured at early postnatal age s through adulthood. Inefficient glucocorticoid inhibitory action on t he immune axis was supported by both the inability of high circulating levels of corticosterone to reduce thymus weight and the failure of d examethasone to influence in vitro thymocyte and splenocyte cell proli feration. 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 po sitive 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) subse t and a decrease in the CD4(-)CD8(+) (T suppressor) subset, was seen. Moreover, in transgenic mice, an absence of sexual dimorphism and a si gnificantly increased immune reactivity were observed. The present stu dy 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(+)CD 8(-) 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 autoaggress ive immune responses and underline the potential modulatory role of se x steroids in this feedback regulation and in the pathogenesis of auto immune diseases.