ArticleJournal of immunology (Baltimore, Md. : 1950)2020
TRAF3 Acts as a Checkpoint of B Cell Receptor Signaling to Control Antibody Class Switch Recombination and Anergy.
Article in Journal of immunology (Baltimore, Md. : 1950), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 24 citations in OpenAlex.
- BCR signal strength governs VH gene replacement in peripheral B cells.Cellular & molecular immunology · 2026Article
- Large-scale GWAS meta-analysis of serum antibody levels in healthy individuals reveals distinct genetic architectures.Genes and immunity · 2026Article
- Syk inhibition limits autoimmunity and abnormal B cell phenotype and function in mice with B cell-specific TRAF3 deficiency.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- Tonsillar expression quantitative trait loci verify and expand genetic contributors to childhood atopic diseases.bioRxiv : the preprint server for biology · 2026Article
- Immunoglobulin class-switch recombination: Mechanism, regulation, and related diseases.MedComm · 2024Review
- Mitochondrial Quality Control Orchestrates the Symphony of B Cells and Plays Critical Roles in B Cell-Related Diseases.Journal of immunology research · 2024Review
- The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy.Genes & diseases · 2024Review
- A review of the literature on the use of CRISPR/Cas9 gene therapy to treat hepatocellular carcinoma.Oncology research · 2024Review
- TRAF2/3 deficient B cells resist DNA damage-induced apoptosis via NF-κB2/XIAP/cIAP2 axis and IAP antagonist sensitizes mutant lymphomas to chemotherapeutic drugs.Cell death & disease · 2023Article
- Upregulated Expression of the IL-9 Receptor on TRAF3-Deficient B Lymphocytes Confers Ig Isotype Switching Responsiveness to IL-9 in the Presence of Antigen Receptor Engagement and IL-4.Journal of immunology (Baltimore, Md. : 1950) · 2023Article
- The adaptor protein TRAF3 is an immune checkpoint that inhibits myeloid-derived suppressor cell expansion.Frontiers in immunology · 2023Article
- TRAF3: A novel regulator of mitochondrial physiology and metabolic pathways in B lymphocytes.Frontiers in oncology · 2023Review
- The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition.Cancers · 2022Article
- Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans withScience immunology · 2022Article
- SARS-CoV-2 booster vaccination rescues attenuated IgG1 memory B cell response in primary antibody deficiency patients.Frontiers in immunology · 2022Article
- Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans.Frontiers in immunology · 2022Review
- Genomic Insights into Myasthenia Gravis Identify Distinct Immunological Mechanisms in Early and Late Onset Disease.Annals of neurology · 2021Article
- How the Signaling Crosstalk of B Cell Receptor (BCR) and Co-Receptors Regulates Antibody Class Switch Recombination: A New Perspective of Checkpoints of BCR Signaling.Frontiers in immunology · 2021Review
- Article
- TNF receptor-associated factor 3 restrains B-cell receptor signaling in normal and malignant B cells.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The BCR recognizes foreign Ags to initiate humoral immunity that needs isotype-switched Abs generated via class switch recombination (CSR); however, stimulating the BCR in the absence of costimulation (e.g., CD40) does not induce CSR; thus, it remains elusive whether and how the BCR induces CSR mechanistically. Autoreactive B cells can maintain anergy via unresponsiveness of their BCRs to self-antigens. However, it remains unknown what molecule(s) restrict BCR signaling strength for licensing BCR-induced CSR and whether deficiency of such molecule(s) disrupts autoreactive B cell anergy and causes B cell-mediated diseases by modulating BCR signaling. In this study, we employ mouse models to show that the BCR's capacity to induce CSR is restrained by B cell-intrinsic checkpoints TRAF3 and TRAF2, whose deletion in B cells enables the BCR to induce CSR in the absence of costimulation. TRAF3 deficiency permits BCR-induced CSR by elevating BCR-proximal signaling intensity. Furthermore, NF-κB2 is required for BCR-induced CSR in TRAF3-deficient B cells but not for CD40-induced or LPS-induced CSR, suggesting that TRAF3 restricts NF-κB2 activation to specifically limit the BCR's ability to induce CSR. TRAF3 deficiency also disrupts autoreactive B cell anergy by elevating calcium influx in response to BCR stimulation, leading to lymphoid organ disorders and autoimmune manifestations. We showed that TRAF3 deficiency-associated autoimmune phenotypes can be rectified by limiting BCR repertoires or attenuating BCR signaling strength. Thus, our studies highlight the importance of TRAF3-mediated restraint on BCR signaling strength for controlling CSR, B cell homeostasis, and B cell-mediated disorders.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.