Glucocorticoids (GCs) are steroid hormones with a broad range of physiologic actions. They are an important component of the physiologic response to stress. In humans and other mammals, the main source of circulating GCs is the adrenal cortex. Adrenal secretion of GCs is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. In response to neural stimuli, corticotropin-releasing hormone (CRH) is released by the hypothalamus into the hypothalamic-hypophyseal portal circulation, and it stimulates production of adrenocorticotrophic hormone (ACTH) by the anterior pituitary. ACTH is released into the systemic circulation, and it stimulates secretion of GCs by cells of the zona fasciculata of the adrenal cortex. GCs and ACTH, in turn, negatively regulate ACTH and CRH secretion, closing the negative-feedback loop. There is also evidence, in mouse and rat models, of de novo synthesis of GCs by other tissues, with local effects including regulation of T cell selection in the thymus and local modulation of T cell activity in the intestinal mucosa [1], [2], [3], [4], [5] (Fig. 1).

GCs are highly lipophilic molecules that readily cross cell membranes. In the cell, their best-known targets are nuclear receptors that function as transcription factors, including the glucocorticoid receptor (GR; gene symbol NR3C1) and the mineralocorticoid receptor (MR; gene symbol NR3C2). While the GR appears to function primarily as a receptor for GCs, the MR also serves as a receptor for the mineralocorticoid aldosterone, which is involved in sodium reabsorption, water retention, potassium excretion, vascular tone, and cardiac remodeling. GC exposure leads to a dramatic re-programming of a cell’s transcriptional output, although the specific genes affected, the magnitude, and even the directionality of the transcriptional response at any given locus vary by cell type [6]. There is also evidence of GC effects that are mediated by mechanisms other than nuclear receptor-mediated regulation of gene expression [7].

Exogenous, synthetic GCs have been the cornerstone of anti-inflammatory and immunosuppressive therapies for the past 75 years [8], [9]. Consequently, the effects of GCs on human immunity have received much more attention from the medical and therapeutic points of view than from that of the physiologic functions for which endogenous GCs evolved. However, there are important differences between endogenous and synthetic GCs, so studies of synthetic GCs offer little information about the physiologic roles of these hormones.

The purpose of this review is to objectively assess existing knowledge about the effects of endogenous GCs on human immunity, scrutinizing existing dogma and highlighting specific knowledge gaps and areas of opportunity for new research. Our emphasis on human studies and on physiologic concentrations of endogenous GCs aims to complement excellent recent reviews of GC effects on immunity, which are centered on the more prevalent studies of endogenous GCs in rodent models, or of synthetic GCs in humans and other species [9], [10].