Glucocorticoid signaling: a nongenomic mechanism for T-cell immunosuppression

Glucocorticoids were long believed to exert their effects through transcriptional regulation of glucocorticoid-receptor target genes. However, there is accumulating evidence for nongenomic glucocorticoid-receptor-dependent modulation of signal transduction pathways. Here, we review rapid glucocorticoid activities and focus on a novel mechanism that underlies nongenomic glucocorticoid-induced immunosuppression in T cells. The findings demonstrate a physical and functional interaction between the glucocorticoid receptor and the T-cell receptor (TCR) complex. In its unligated state, the glucocorticoid receptor has an important role in TCR signaling but, after glucocorticoid-receptor–ligand binding (caused by short-term treatment with the synthetic glucocorticoid dexamethasone), the TCR complex is disrupted, leading to impaired TCR signaling. These data reveal a dichotomal functional role for glucocorticoid receptors: one in the cytosol as part of the TCR complex and the other as a nuclear regulator of gene transcription. Drugs that selectively target membrane-bound glucocorticoid receptors might represent a novel immunosuppressive approach.