Cell-intrinsic regulation of murine dendritic cell function and survival by prereceptor amplification of glucocorticoid

Although the inhibitory effects of therapeutic glucocorticoids (GCs) on dendritic cells (DCs) are well established, the roles of endogenous GCs in DC homeostasis are less clear. A critical element regulating endogenous GC concentrations involves local conversion of inactive substrates to active 11-hydroxyglucocorticoids, a reduction reaction catalyzed within the endoplasmic reticulum by an enzyme complex containing 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) and hexose-6-phosphate dehydrogenase (H6PDH). In this study, we found that this GC amplification pathway operates both constitutively and maximally in steady state murine DC populations and is unaffected by additional inflammatory stimuli. Under physiologic conditions, 11 beta HSD1-H6PDH increases the sensitivity of plasmacytoid DCs (pDCs) to GC-induced apoptosis and restricts the survival of this population through a cell-intrinsic mechanism. Upon CpG activation, the effects of enzyme activity are overridden, with pDCs becoming resistant to GCs and fully competent to release type I interferon. CD8 alpha(+) DCs are also highly proficient in amplifying GC levels, leading to impaired maturation following toll-like receptor-mediated signaling. Indeed, pharmacologic inhibition of 11 beta HSD1 synergized with CpG to enhance specific T-cell responses following vaccination targeted to CD8 alpha(+) DCs. In conclusion, amplification of endogenous GCs is a critical cell-autonomous mechanism for regulating the survival and functions of DCs in vivo.