Potential cellular immunotherapies to suppress inhibitor formation in factor replacement therapy for hemophilia based on the engineering of T cells that have emerged from preclinical studies. In preclinical studies, T cells were gene-modified ex vivo by viral gene transfer, expanded, and subsequently transplanted to suppress inhibitor formation. These approaches seek to generate antigen-specific Tregs, as shown in several proof-of-principle studies on FVIII. Examples include redirection of antigen-specificity by transduction of CD4⁺FoxP3⁺ Tregs with FVIII-specific chimeric antigen receptor or T-cell receptor fusion construct (TRuC), which avoids major histocompatibility complex restrictions (top left); or with FVIII-specific TCR (top right). B-cell antigen receptors (BARs) use a portion of FVIII so that gene-modified CD4⁺FoxP3⁺ Tregs suppress FVIII-specific B cells (which express B-cell receptors for FVIII; bottom right). Alternatively, the introduction of a BAR to CD8⁺ T cells enables these cytolytic cells to eliminate FVIII-specific B cells (bottom right). Finally, expanded FVIII-specific effector CD4⁺ T cells can be reprogrammed to become Tregs by FoxP3 gene transfer (bottom left).