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Updated: May 21, 2025

Retroviral Transduction of Helper T Cells as a Genetic Approach to Study Mechanisms Controlling their Differentiation and Function
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Dominant interfering CARD11 variants disrupt JNK signaling to promote GATA3 expression in T cells

Bradly M Bauman1,2, Jeffrey R Stinson1,2, Melissa A Kallarakal1

  • 1Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

The Journal of Experimental Medicine
|March 20, 2025
PubMed

Insights

Defects in CARD11 protein signaling cause severe atopy. Impaired CARD11-JNK signaling enhances T helper 2 cell development by increasing GATA3 expression in patients with CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Primary atopic disorders are linked to genetic defects affecting T-cell receptor (TCR) signaling.
  • CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease results from CARD11 variants causing severe atopy.
  • The role of CARD11-dependent JNK signaling in T cells is not well understood.

Purpose of the Study:

  • To investigate the function of CARD11-dependent JNK signaling in T cells.
  • To elucidate the mechanism by which CARD11 variants contribute to TH2 cell differentiation in CADINS disease.

Main Methods:

  • Assessed TCR-induced activation of JNK1/JNK2 and AP-1 family members.
  • Analyzed the impact of patient-derived CARD11 variants on JNK signaling.
  • Utilized transcriptome profiling to identify downstream effects of JNK signaling inhibition.
  • Measured GATA3 expression in T cells from CADINS patients.

Main Results:

  • CARD11 is essential for TCR-induced JNK1/JNK2 and AP-1 activation.
  • CARD11 variants impair both NF-κB and JNK signaling pathways.
  • JNK signaling inhibition upregulates TCR-induced GATA3 and NFATC1 expression.
  • CADINS patient T cells exhibit increased GATA3 expression due to impaired CARD11-JNK signaling.

Conclusions:

  • CARD11 critically regulates TCR-induced JNK signaling in T cells.
  • Impaired CARD11-JNK signaling promotes TH2 cell differentiation through enhanced GATA3 induction.
  • This study reveals a novel mechanism linking CARD11 dysfunction to atopic disease pathogenesis.

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