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

  • Cell Commun Signal. 2025 Jun 4;23(1):268. doi: 10.1186/s12964-025-02266-0.
L Tatiana Albarracin Melo  1  2 ,  Nekruz Abdulkhakov  1 ,  Irina Han  2  3 ,  Ali El-Bizri  1 ,  Monika Brunner-Weinzierl  2  3 ,  Burkhart Schraven  1  2 ,  Luca Simeoni  4  5
Affiliations
  • 1. Institute of Molecular and Clinical Immunology, Medical Faculty, University Hospital, Otto-Von Guericke University, Magdeburg, Germany.
  • 2. Health Campus Immunology, Infectiology and Inflammation (GC-I3), Medical Faculty, University Hospital, Otto-Von Guericke University, Magdeburg, Germany.
  • 3. Department of Experimental Pediatrics, Medical Faculty, University Hospital, Otto-Von-Guericke-University, Magdeburg, Germany.
  • 4. Institute of Molecular and Clinical Immunology, Medical Faculty, University Hospital, Otto-Von Guericke University, Magdeburg, Germany. [email protected].
  • 5. Health Campus Immunology, Infectiology and Inflammation (GC-I3), Medical Faculty, University Hospital, Otto-Von Guericke University, Magdeburg, Germany. [email protected].
PMID: 40468327 DOI: 10.1186/s12964-025-02266-0
Abstract

Background: Glucocorticoids (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.

Methods: 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.

Results: 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 CA2+ 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 4-6 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.

Conclusions: 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.

Keywords
Erk1/2 activation; Glucocorticoids; IL-2 signaling; Immunosuppression; IκB activation; Jak/STAT pathway; T cells; TCR signaling.
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