Interactions between engineered Tregs and effector T cells (Teffs). A gene construct encoding for a T-cell receptor (TCR) specific for FVIII peptide is transduced into polyclonal Tregs, producing Tregs expressing that TCR. Tregs interact with antigen-presenting cells (APCs) via human major histocompatibility complex II (MHCII), as do Teffs. Tregs exert suppressive effects on Teffs, preventing immune responses to antigen and promoting tolerance. Kim et al demonstrate in vitro that such engineered Tregs can suppress the typically polyclonal responses to whole FVIII, despite expressing TCRs specific for a single small FVIII peptide. Could this result in the off-target suppression of T-cell responses to non-FVIII antigens, such as antigens from pathogens or vaccines?