A20 Intrinsically Influences Human Effector T-cell Survival and Function by Regulating Both NF-κB and JNK Signaling
EUROPEAN JOURNAL OF IMMUNOLOGY(2024)
Abstract
A20 is a dual-function ubiquitin-editing enzyme that maintains immune homeostasis by restraining inflammation. Although A20 serves a similar negative feedback function for T-cell receptor (TCR) signaling, the molecular mechanisms utilized and their ultimate impact on human T-cell function remain unclear. TCR engagement triggers the assembly of the CARD11-BCL10-MALT1 (CBM) protein complex, a signaling platform that governs the activation of downstream transcription factors including NF-kappa B and c-Jun/AP-1. Utilizing WT and A20 knockout Jurkat T cells, we found that A20 is required to negatively regulate NF-kappa B and JNK. Utilizing a novel set of A20 mutants in NF-kappa B and AP-1-driven reporter systems, we discovered the ZnF7 domain is crucial for negative regulatory capacity, while deubiquitinase activity is dispensable. Successful inactivation of A20 in human primary effector T cells congruently conferred sustained NF-kappa B and JNK signaling, including enhanced upregulation of activation markers, and increased secretion of several cytokines including IL-9. Finally, loss of A20 in primary human T cells resulted in decreased sensitivity to restimulation-induced cell death and increased sensitivity to cytokine withdrawal-induced death. These findings demonstrate the importance of A20 in maintaining T-cell homeostasis via negative regulation of both NF-kappa B and JNK signaling. The ubiquitin-editing enzyme A20 regulates innate and adaptive immune receptor signaling, but its intrinsic function in human T cells is poorly understood. We show that A20 deletion enhances cytokine secretion and alters apoptosis sensitivity in primary human T cells by modulating NF-kB and JNK/AP-1 signaling downstream of the CARD11-BCL10-MALT1 complex. image
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Key words
Apoptosis,Cellular immunology,Cytokines,Signal transduction,T cells
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