The immunosuppressive effect of glucocorticoids in human primary T cells is mainly mediated via a rapid inhibition of the IL-2/IL-2R signaling axis.

backgroundGlucocorticoids (GCs) are highly effective anti-inflammatory drugs that suppress T-cell activation, cytokine production, and T-cell proliferation. Nevertheless, at which molecular level and how fast GCs exert their immunosuppressive effect in T cells still remains elusive, as inconsistent genomic and non-genomic mechanisms of action have been proposed. One model postulates that GCs quickly inhibit proximal T-cell receptor (TCR) signaling via a non-genomic mechanism, whereas others have shown a strong inhibition of interleukin-2 (IL-2) transcription at later stages of T-cell activation. Due to their therapeutic significance, we have decided to shed light onto this issue and investigated how fast and at which level GCs inhibit T-cell activation by analyzing TCR and IL-2 signaling.

methodsWe utilized primary human T cells isolated from healthy donors, which were stimulated with immobilized CD3/CD28 antibodies. These cells were treated with three different GCs, diflorasone, dexamethasone, and prednisolone.

resultsAnalyses of signaling kinetics revealed that GCs did not affect early TCR signaling as suggested by the normal phosphorylation levels of lymphocyte-specific protein tyrosine kinase (Lck), zeta-chain-associated protein kinase 70 (Zap70), linker for activation of T cells (LAT), and unchanged Ca

conclusionsOur study, by showing that GCs rapidly suppress the IL-2/IL-2R expression and signaling without significantly affecting proximal TCR signaling, has highlighted a clear mechanism of action of GCs that contributes to their therapeutic efficacy.