Genetic identification of the FcδR complex: TRβV12-4 as the IgD-binding domain targeted for immunotherapy in rheumatoid arthritis

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disease that drives progressive joint destruction and functional disability. Current therapies are often limited by inadequate efficacy and risks of broad immunosuppression. Immunoglobulin D (IgD) is a conserved antibody isotype with poorly understood functions. We previously reported aberrant IgD secretion in RA and its capacity to activate T cells, yet the putative IgD receptor (FcδR) remained unidentified. OBJECTIVES: To identify and characterize FcδR, elucidate the molecular mechanisms involved in T-cell activation, define its pathogenic role in RA, and evaluate its therapeutic potential as a new target. METHODS: FcδR was identified by affinity pull-down using IgD-Fc as bait, followed by mass spectrometry analysis. Molecular interactions were further confirmed by molecular docking, surface plasmon resonance (SPR) analysis and co-immunoprecipitation. IgD-triggered signaling was analyzed using CRISPR/Cas9-engineered TRβV12-4 knockout and overexpression cells. Therapeutic blockade was evaluated using IgD-Fc-Ig as a competitive antagonist in vitro and in vivo using AAV-mediated FcδR-overexpressing collagen-induced arthritis (CIA) mouse model. RESULTS: FcδR was identified as a heteromeric complex of TRβV12-4 with CD3ε/CD3ζ. IgD binding to TRβV12-4 activated T cells via CD3-mediated Lck-ZAP70 signaling. The IgD-Fc-Ig fusion protein competitively blocked IgD-FcδR interaction, suppressing pathological T-cell activation. In CIA mice, FcδR expression correlated with inflammatory severity, and FcδR blockade via IgD-Fc-Ig administration significantly attenuated arthritic progression. CONCLUSION: This study identifies FcδR as a previously unrecognized IgD Fc receptor complex comprising TRβV12-4 and CD3ε/CD3ζ, triggering T-cell activation via IgD and driving RA pathogenesis. IgD-Fc-Ig competitively blocks IgD-FcδR and exerts therapeutic effects in CIA. These findings establish FcδR as a novel therapeutic target and a promising strategy for RA treatment.