77. Glucocorticoid receptor signaling is responsible for the circadian decline in naïve T cell numbers and increase in CXCR4 expression in the morning hours

Abstract

One of the most pronounced circadian rhythms in human immune parameters is the decline in naïve T cell numbers from early night to morning. It is believed to be a consequence of CXCR4 up-regulation on T cells in the morning by cortisol with a subsequent extravasation of the cells. However, a systematic evaluation of this assumption is lacking. We therefore investigated in two human studies the consequences of blocking endogenous cortisol activity at glucocorticoid receptors (GR). This was done either by reducing cortisol levels with the cortisol-synthesis-inhibitor metyrapone or by administration of the GR antagonist mifepristone. In both studies, the morning increase in CXCR4 expression on naïve T cells was reduced or completely blocked after drug treatment. The parallel decline in naïve T cell numbers was also disturbed, although after mifepristone this result was less consistent. However, this might be due to the partial agonistic properties of mifepristone, which we observed in the early night and which we further characterized in subsequent in vitro experiments. To sum, we showed that endogenous cortisol, via activation of GR, mediates the circadian changes in naïve T cell numbers and CXCR4 expression. CXCR4 was revealed as a highly sensitive marker of GR signaling, and might be used in the future for drug monitoring. Additionally, we found partial agonistic effects after low-dose mifepristone treatment that depended on endogenous cortisol concentrations.