Monoepitopic and oligoclonal T-cell responses to therapeutic FVIII. (A) The immune response to FVIII requires antigen internalization by APCs, processing in endosomes, and FVIII-derived peptides binding to HLA for presentation at the cell surface. A competition for binding to HLA thus occurs within the intracellular pool of FVIII-derived and non-FVIII-derived peptides. (B) For the immune response to develop, and leaving aside the requisite for danger signals that allow the maturation of APCs, there is a need for an appropriate T-cell repertoire. The expressed T-cell repertoire is shaped by positive and negative selection in the thymus, and encounter of antigens at the periphery. It is thus incomplete and may lack critical epitope specificities. In our example, the immunodominant green and orange FVIII peptides outrange other peptides, such as the subdominant dark-blue peptide, for HLA binding, and are exposed at the surface. The potential T-cell repertoire has been selected: T cells specific for the orange peptide have been eliminated, whereas that specific for the green peptide have been retained, thus allowing initiation of a T-cell–mediated anti-FVIII immune response. Presumably, the immune system of a patient with severe hemophilia A without circulating FVIII is not educated against FVIII, and the expressed repertoire of FVIII-reactive T cells has not been deleted. (C) Deimmunization of FVIII would rely on the modification of dominant T-cell epitopes (eg, green epitope changed into purple). The FVIII would then be “invisible” to T cells, provided that subdominant epitopes are not presented by HLA in the absence of the dominant epitope. (D) Nanoparticles coated with MHCII-bound FVIII immunodominant epitope(s) could trigger the generation and expansion of antigen-specific type 1 regulatory CD4⁺ T cells.