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Updated: May 11, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

Superantigen-induced steroid resistance depends on activation of phospholipase Cβ2

Auke P Verhaar1, Manon E Wildenberg, Marjolijn Duijvestein

  • 1Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2300RC Leiden, The Netherlands.

Journal of Immunology (Baltimore, Md. : 1950)
|May 22, 2013
PubMed

Insights

Glucocorticoids inhibit T cell receptor (TCR) signaling via Lck. However, superantigens activate an alternative pathway, making T cells resistant to these steroids and bypassing Lck-dependent signaling.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Glucocorticoid receptors associate with T cell receptor (TCR) complexes, inhibiting Lck-dependent signaling through a non-genomic mechanism.
  • Activated T cells can become steroid-resistant, particularly when stimulated by superantigens, which may involve alternative signaling pathways.
  • The relative contribution of non-genomic versus transcriptional effects of glucocorticoids on T cell activation remains unclear.

Purpose of the Study:

  • To investigate the mechanism by which superantigens confer steroid resistance to T cells.
  • To determine if a noncanonical signaling pathway bypasses Lck-dependent TCR signaling and glucocorticoid inhibition.
  • To explore the role of G protein-coupled phospholipase C (PLC)β in T cell activation and steroid resistance.

Main Methods:

  • Utilized human T cells stimulated with staphylococcal enterotoxin B (SEB).
  • Investigated the activation of Gαq and PLCβ2 pathways.
  • Assessed the impact of PLCβ inhibition (U-73122) on SEB-induced T cell activation and steroid sensitivity in vitro and in vivo.

Main Results:

  • SEB activates a Gαq and PLCβ2-dependent pathway in human T cells.
  • This noncanonical pathway is independent of Lck-PLCγ signaling and confers resistance to glucocorticoids.
  • Inhibition of PLCβ sensitized SEB-treated mice to dexamethasone, indicating the pathway's role in vivo.

Conclusions:

  • Glucocorticoid effects on TCR-induced T cell proliferation are primarily non-genomic.
  • Activation of an Lck-independent, G protein-PLCβ-dependent pathway by superantigens bypasses glucocorticoid inhibition.
  • Targeting this alternative pathway could restore glucocorticoid sensitivity in steroid-resistant T cells.

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