Dual cellular targeting of complement receptor 2 (CR2/CD21) synergistically suppresses autoreactive germinal center activity and autoimmunity in lupus

Pathogenic germinal center (GC) activity persists in systemic lupus erythematosus (SLE) because current B cell-targeting therapies do not consistently eliminate the resilient GC niche that sustains autoimmunity. Complement receptor 2 (CR2/CD21) presents a unique bicellular therapeutic target to impede GC-associated autoimmune disease. For B cells, it has been previously shown to lower the threshold for B cell activation, and for follicular dendritic cells (FDCs), it sustains the GC response. Using a CD21-blocking antibody in a spontaneous lupus-prone mouse model, we demonstrate that dual CD21 blockade on both B cells and FDCs synergistically inhibited GC B cell responses and suppressed autoantibody production, memory recall, and renal antibody deposition. Mechanistically, B cell-specific blockade impaired GC entry by limiting initial activation, whereas FDC-specific blockade disrupted GC architecture and curtailed ongoing responses. Further, dual blockade uniquely reshaped immunological memory by promoting accumulation of a CD21low/-CD38+ memory B cell subset with attenuated antibody-secreting cell (ASC) recall potential. These findings identify CD21 blockade as a precision immunomodulatory strategy capable of suppressing pathogenic humoral immunity without complete B cell depletion.