Pancreatic islet-specific engineered T regs exhibit robust antigen-specific and bystander immune suppression in type 1 diabetes models.

Adoptive transfer of regulatory T cells (T) is therapeutic in type 1 diabetes (T1D) mouse models. T that are specific for pancreatic islets are more potent than polyclonal T in preventing disease. However, the frequency of antigen-specific natural T is extremely low, and ex vivo expansion may destabilize T, leading to an effector phenotype. Here, we generated durable, antigen-specific engineered T (EngT) from primary human CD4 T cells by combining homology-directed repair editing and lentiviral T cell receptor (TCR) delivery. Using TCRs derived from clonally expanded CD4 T cells isolated from patients with T1D, we generated islet-specific EngT that suppressed effector T cell (T) proliferation and cytokine production. EngT suppressed T recognizing the same islet antigen in addition to bystander T recognizing other islet antigens through production of soluble mediators and both direct and indirect mechanisms. Adoptively transferred murine islet-specific EngT homed to the pancreas and blocked diabetes triggered by islet-specific T or diabetogenic polyclonal T in recipient mice. These data demonstrate the potential of antigen-specific EngT as a targeted therapy for preventing T1D.