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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Analyses 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\n                      <jats:sup>2+<\/jats:sup>\n                      influx. Conversely, we found that GCs strongly and rapidly suppressed the activation of the Janus kinase (Jak)\/ signal transducer and activator of transcription (STAT) pathway within 4\u20136 h upon CD3\/CD28 stimulation in primary human T cells. This observation was in line with a strong inhibition of cytokine production and with the impaired upregulation of the IL-2 receptor (IL-2R) upon GC treatment, thus resulting in the abrogation of T-cell proliferation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-025-02266-0","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T14:47:29Z","timestamp":1749048449000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["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"],"prefix":"10.1186","volume":"23","author":[{"given":"L. 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