Dexamethasone Modulates TCR ζ Chain Expression and Antigen Receptor-Mediated Early Signaling Events in Human T Lymphocytes

Dexamethasone is a potent anti-inflammatory and immunosupressive agent that has complex, yet incompletely defined, effects on the immune response. Here, we explored the effect of dexamethasone on the expression of TCR ζ chain and TCR/CD3-induced early signaling events in human T lymphocytes. Immunoblotting studies using TCR ζ chain specific mAb showed a dose-dependent biphasic effect of dexamethasone on TCR ζ chain expression, that is, it was increased when cells were incubated with 10 nM, whereas the expression was decreased when incubated with 100 nM dexamethasone. The dose-dependent biphasic effect of dexamethsone on the TCR ζ chain expression was also revealed by FACS analysis of permeabilized cells. Time course studies showed that upregulation of the TCR ζ chain at 10 nM dexamethasone reached maximum levels at 24 h and remained elevated up to 48 h. Other subunits of the TCR/CD3 complex were minimally affected under these conditions. The increased expression of the TCR ζ chain following treatment with 10 nM dexamethasone correlated with increased anti-CD3 antibody-induced tyrosine phosphorylation of the TCR ζ chain and downstream signaling intermediate ZAP-70 and PLCγ with faster kinetics. Similarly, the induction of TCR ζ chain expression at 10 nM dexamethasone correlated with increased and more sustained TCR/CD3-mediated [Ca2+]i response. Reporter gene assays using TCR ζ chain promoter-driven luciferase gene constructs in Jurkat cells showed that treatment with 10 nM dexamethasone increased TCR ζ chain promoter activity and that the region between −160 and +58 was responsible for the observed effect. These results suggest that dexamethasone primarily acts at the transcriptional level and differentially modulates TCR ζ chain expression and antigen receptor-mediated early signaling events in human peripheral T lymphocytes.