Dominant interfering CARD11 variants disrupt JNK signaling to promote GATA3 expression in T cells
Several "primary atopic disorders" are linked to monogenic defects that attenuate TCR signaling, favoring T helper type 2 (TH2) cell differentiation. Patients with CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease suffer from severe atopy, caused by germline loss-of-function/dominant interfering (LOF/DI) CARD11 variants. The CARD11 scaffold enables TCR-induced activation of NF-κB, mTORC1, and JNK signaling, yet the function of CARD11-dependent JNK signaling in T cells remains nebulous. Here we show that CARD11 is critical for TCR-induced activation of JNK1 and JNK2, as well as canonical JUN/FOS AP-1 family members. Patient-derived CARD11 DI variants attenuated WT CARD11 JNK signaling, mirroring effects on NF-κB. Transcriptome profiling revealed JNK inhibition upregulated TCR-induced expression of GATA3 and NFATC1, key transcription factors for TH2 cell development. Further, impaired CARD11-JNK signaling was linked to enhanced GATA3 expression in CADINS patient T cells. Our findings reveal a novel intrinsic mechanism connecting impaired CARD11-dependent JNK signaling to enhanced GATA3/NFAT2 induction and TH2 cell differentiation in CADINS patients.
Authors
- Joshua D. Milner (ORCID: https://orcid.org/0000-0002-3913-3869)
- Andrew L. Snow (ORCID: https://orcid.org/0000-0002-8728-6691)
- Clifton L. Dalgard (ORCID: https://orcid.org/0000-0003-2025-8239)
- Melissa A. Kallarakal (ORCID: https://orcid.org/0009-0000-9948-3871)
- Bradly M. Bauman (ORCID: https://orcid.org/0000-0002-4471-0966)
- Lei Huang (ORCID: https://orcid.org/0000-0002-1491-3869)
- Nermina Saucier (ORCID: https://orcid.org/0009-0004-8992-1427)
- Andrew M. Frank (ORCID: https://orcid.org/0000-0003-0411-7102)
- Megan A. Cooper (ORCID: https://orcid.org/0000-0002-5696-172X)
- Jeffrey R. Stinson (ORCID: https://orcid.org/0000-0002-4157-3185)
- Alice Chan (ORCID: https://orcid.org/0000-0003-1466-7044)
- Gauthaman Sukumar (ORCID: https://orcid.org/0000-0003-3129-4171)
Institutions
- Henry M. Jackson Foundation (US)
- Uniformed Services University of the Health Sciences (US)
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- Columbia University Irving Medical Center (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1084/jem.20240272
- Citations
- 5
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 3.19
Funders
- U.S. Department of Defense
- Jeffrey Modell Foundation
- Amgen
- National Institutes of Health
- Uniformed Services University of the Health Sciences
- National Cancer Institute