TNFRSF13C

Detailed Information

The TNFRSF13C gene is located on human chromosome 22q13.1-q13.31 and encodes the B-cell activating factor receptor (BAFFR), also referred to as CD268 or BR3. This gene comprises at least three exons and produces a 123-bp transcript (NM_052945.4), which is ultimately translated into a 184-amino-acid single-pass transmembrane protein. As a type III transmembrane protein, BAFFR contains an extracellular cysteine-rich domain (CRD) characteristic of the TNF receptor superfamily, stabilized by disulfide bonds to provide the structural basis for ligand binding. Unlike some other TNFRSF members, BAFFR lacks an intracellular death domain and instead has a short cytoplasmic tail, suggesting that its downstream signaling depends on adaptor proteins. At the protein level, BAFFR exists as a monomer but undergoes oligomerization upon ligand binding, forming signaling-competent complexes. Compared with related receptors such as BCMA (TNFRSF17) and TACI (TNFRSF13B), BAFFR displays higher binding specificity to its ligand BAFF, which arises from unique loop structures and hydrophobic interfaces within its CRD2 domain.

Expression Patterns and Evolutionary Conservation

BAFFR expression is highly cell type-specific and is largely confined to B lymphocytes. During B-cell development, BAFFR expression emerges at the transitional stage, peaks in mature follicular and marginal zone B cells, and is downregulated in plasma cells. This stage-dependent expression highlights its essential role in B-cell maturation and survival. From an evolutionary perspective, BAFFR is strongly conserved among mammals but shows reduced conservation in birds and reptiles, reflecting adaptive immune system divergence. Structural studies reveal that BAFFR's CRD forms a distinctive β-sandwich fold, in which the Cys109 residue is crucial for structural stability. Mutations at this site abolish receptor function, providing a structural framework for understanding BAFF-BAFFR interactions and for developing therapeutic inhibitors.

Biological Functions and Signaling Pathways

As the primary high-affinity receptor for BAFF, BAFFR plays a non-redundant role in maintaining the survival and homeostasis of mature B cells. The receptor primarily activates two NF-κB pathways: the classical and the non-classical. In the classical pathway, BAFFR trimerization recruits TRAF2/TRAF3 complexes, stabilizes NIK, and activates IKK, leading to nuclear translocation of the p50-RelA heterodimer and transcription of survival genes. In the non-classical pathway, BAFFR promotes processing of p100 into p52, which forms p52-RelB heterodimers that regulate genes essential for B-cell development. Together, these pathways suppress apoptosis, enhance metabolic adaptation, and sustain B-cell survival in peripheral immune organs. Knockout mouse studies confirm that BAFFR deficiency results in a drastic reduction of mature B cells and impaired antibody responses, while other lymphocyte subsets remain unaffected.

Figure 1. BAFFR-induced intracellular signaling. (Smulski CR, et al., 2018)

Regulation and Crosstalk with BCR Signaling

BAFFR signaling is tightly regulated at multiple levels. On the cell surface, proteolytic cleavage generates soluble decoy receptors that compete for BAFF and dampen signaling. Internally, ligand-induced receptor endocytosis terminates signaling and directs BAFFR toward lysosomal degradation. The receptor also shows differential ligand binding kinetics compared to BCMA and TACI: BAFF trimers bind three BAFFR monomers, whereas BAFF 60-mers engage multiple BAFFR complexes through a virus-like assembly, amplifying signaling at low ligand concentrations. Moreover, BAFFR signaling intersects with BCR signaling; BCR activation upregulates BAFFR, while BAFFR enhances BCR responsiveness, forming a positive feedback loop that sustains B-cell pools and germinal center responses but predisposes to autoimmune activation.

Pathological Roles and Disease Associations

Dysregulation of the BAFF-BAFFR axis is strongly implicated in autoimmune disease. In systemic lupus erythematosus (SLE), serum BAFF levels are markedly elevated, promoting the survival of autoreactive B cells that escape negative selection, mature in peripheral tissues, and differentiate into plasma cells producing pathogenic autoantibodies such as anti-dsDNA. These autoantibodies form immune complexes that deposit in tissues such as the kidney and skin, driving inflammatory damage. BAFF transgenic mice develop expanded mature B-cell pools, lupus-like nephritis, and autoantibodies, further validating the causal role of BAFFR hyperactivation. In humans, BAFF levels correlate with disease activity index and BAFFR expression density correlates with autoantibody titers. Beyond autoimmunity, loss-of-function TNFRSF13C mutations cause common variable immunodeficiency type 4 (CVID4), characterized by hypogammaglobulinemia, impaired antibody responses, and recurrent infections, with B-cell development arrested at the transitional stage. In malignancies, BAFFR expression supports tumor survival in chronic lymphocytic leukemia (CLL) through autocrine BAFF signaling, and in mantle cell lymphoma (MCL), BAFFR-mediated NF-κB activation confers chemoresistance. EBV and related herpesviruses further exploit this pathway by encoding viral homologs that sequester BAFF, suppressing BAFFR signaling and aiding immune evasion.

Clinical Translation and Therapeutic Targeting

Targeting the BAFF-BAFFR axis has yielded therapeutic advances in autoimmunity. Belimumab, the first approved BAFF inhibitor, is a humanized monoclonal antibody that neutralizes soluble BAFF, preventing its interaction with BAFFR, BCMA, and TACI. In phase III SLE trials, belimumab improved response rates, reduced flares, and lowered autoantibody titers while depleting autoreactive B cells. Other agents, such as VAY736, a BAFFR-specific monoclonal antibody, are under development and may provide broader inhibition by blocking both soluble and membrane-bound BAFF and inducing ADCC. In oncology, bispecific antibodies linking BAFFR to CD3 redirect T cells against BAFFR-expressing tumor cells, while antibody–drug conjugates (e.g., BAFFR-MMAE) selectively eliminate malignant B cells. CAR-T strategies targeting BAFFR are also being tested in preclinical B-cell lymphoma models, with promising efficacy, though off-tumor toxicity remains a concern.

Challenges and Future Directions

Despite extensive progress, critical questions remain regarding BAFFR signaling. Its short cytoplasmic tail lacks a death domain, raising questions about how it effectively recruits TRAFs and coordinates NF-κB pathways. A conserved "PVPAT" motif has been identified as a docking site for IKK complexes, but the broader scaffolding network remains unresolved. The spatiotemporal dynamics of BAFFR signaling in specialized microenvironments such as germinal centers also require further study, and single-cell technologies may provide new insights. The role of BAFFR in regulatory B cells (Bregs) and immune tolerance is another emerging area. Translationally, long-term BAFF inhibition risks hypogammaglobulinemia and infection, emphasizing the need for more selective strategies such as localized delivery, conditionally activatable drugs, or small-molecule allosteric modulators. Precision approaches guided by biomarkers such as BAFFR expression and genetic variants will be key to tailoring therapies. Ultimately, integrated multi-omics mapping of BAFFR signaling will enable deeper mechanistic understanding and individualized intervention in autoimmunity, immunodeficiency, and B-cell malignancies.