ArticleTranslational pediatrics2025
The impact of NF-κB2 mutations on Tfh cell differentiation and their critical role in immune function.
Article in Translational pediatrics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: The non-canonical NF-κB2 pathway is crucial for immune regulation, and pathogenic mutations in NF-κB2 are linked to common variable immunodeficiency (CVID), recurrent infections, and autoimmune diseases. T follicular helper (Tfh) cells play a key role in B cell differentiation and antibody production, but the effects of NF-κB2 mutations on Tfh cell differentiation remain unclear. This study investigates the clinical and functional consequences of two NF-κB2 mutations: c.1714G>A (p.A572T) and c.2540dupT (p.R848Efs*38). Methods: We analyzed clinical features, immunophenotypes, and endocrine profiles of three patients carrying NF-κB2 mutations. Transcriptome sequencing of peripheral blood mononuclear cells (PBMCs) from Patient 3 (P3) and five healthy donors was performed to examine gene expression changes. Flow cytometry quantified Tfh cell populations, and real-time quantitative polymerase chain reaction (RT-qPCR) validated the expression of genes involved in Tfh differentiation. The impact of NF-κB2 mutations on p100 processing and nuclear translocation was assessed via western blot and immunofluorescence in HEK293T cells. Results: Patient 1 (P1) exhibited mild clinical features, primarily asthma, while Patient 3 (P3) presented with severe immunodeficiency, recurrent pulmonary infections, and hormonal deficiencies. Transcriptome sequencing revealed significant downregulation of T cell differentiation pathways in P3, particularly Tfh-related genes such as Conclusions: This study identifies novel mechanisms by which NF-κB2 mutations impair immune function. The R848Efs*38 mutation disrupts Tfh cell differentiation by interfering with p100 processing and reducing key Tfh-related transcription factors. These findings enhance our understanding of NF-κB2-related immunodeficiencies and their molecular underpinnings, contributing to the broader knowledge of immune regulation and potential therapeutic targets.
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