Gene-modified CD4⁺CD25⁺FoxP3⁺ Tregs expressing a CAR against FVIII suppress CD4⁺ T cells with FVIII-specific TCR and B-cell responses against FVIII. These interactions result in suppression of antibody formation against FVIII. Binding of intact FVIII protein to the CAR, possibly on the surface of an APC, stimulates the Tregs to suppress. It is possible that direct suppression of B cells with FVIII bound to their B-cell receptor (BCR) also occurs. IL2R, interleukin-2 receptor; MHC II, major histocompatibility complex II.