Bauman Bradly M, Stinson Jeffrey R, Kallarakal Melissa A, Huang Lei Haley, Frank Andrew M, Sukumar Gauthaman, Saucier Nermina, Dalgard Clifton L, Chan Alice Y, Milner Joshua D, Cooper Megan A, Snow Andrew L
Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Henry M. Jackson Foundation for the Advancement of Military Medicine , Bethesda, MD, USA.
J Exp Med. 2025 Jun 2;222(6). doi: 10.1084/jem.20240272. Epub 2025 Mar 20.
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.
几种“原发性特应性疾病”与单基因缺陷有关，这些缺陷会减弱TCR信号传导，有利于2型辅助性T（TH2）细胞分化。患有与CARD11相关的特应性疾病且伴有NF-κB信号传导显性干扰（CADINS）的患者患有严重特应性疾病，这是由种系功能丧失/显性干扰（LOF/DI）CARD11变体引起的。CARD11支架能够实现TCR诱导的NF-κB、mTORC1和JNK信号传导激活，但CARD11依赖性JNK信号传导在T细胞中的功能仍不明确。在这里，我们表明CARD11对于TCR诱导的JNK1和JNK2激活以及经典的JUN/FOS AP-1家族成员至关重要。患者来源的CARD11 DI变体减弱了野生型CARD11 JNK信号传导，这与对NF-κB的影响相似。转录组分析显示，JNK抑制上调了TCR诱导的GATA3和NFATC1的表达，这是TH2细胞发育的关键转录因子。此外，受损的CARD11-JNK信号传导与CADINS患者T细胞中GATA3表达增强有关。我们的研究结果揭示了一种新的内在机制，将受损的CARD11依赖性JNK信号传导与CADINS患者中增强的GATA3/NFAT2诱导和TH2细胞分化联系起来。
