Effects of mifepristone on T cell subsets in humans

Abstract

In humans, blood T cell numbers are highest at 2 AM and lowest at 11 PM. This rhythm mainly reflects changes in numbers of CD4 and CD8 naive (TN) and central memory T cells (TCM) that are reduced due to rising cortisol levels in the morning. Preliminary data indicate that cortisol induces an upregulation of CXCR4 on TN and TCM and, thereby, redirection of these cells to the bone marrow. To elucidate whether this effect is mediated by the glucocorticoid receptor (GR) we administered the GR antagonist mifepristone (MIF, 200 mg) in a randomized placebo controlled study at 11 PM to 16 healthy young men and monitored T cell subsets until 9:30 AM. In the placebo condition, cortisol and CXCR4 increased in the morning while TN and TCM counts showed a concomitant decline. Unexpectedly, MIF failed to prevent these morning changes in CXCR4 and T cell numbers, presumably, due to enhanced cortisol levels. At night, MIF even showed partial agonistic actions with increases in CXCR4. In a second experiment we took blood from 13 healthy young men at night and in the morning and measured CXCR4 expression on T cell subsets after culturing cells in the presence or absence of MIF. Again, MIF increased CXCR4 on TN and TCM at night. In contrast, MIF clearly suppressed CXCR4 on these T cell subpopulations in the morning. The latter finding corroborates the assumption that systemic increases in cortisol counteracted the GR antagonistic effects of MIF on CXCR4 in the in vivo experiment.