Pancreatic islet-specific engineered T <sub>regs</sub> exhibit robust antigen-specific and bystander immune suppression in type 1 diabetes models
Soo Jung Yang, Akhilesh K. Singh, Travis Drow, Tori Tappen, Yuchi Honaker, Fariba Barahmand-pour-Whitman, Peter S. Linsley, Karen Cerosaletti, Kelsey E. Mauk, Yufei Xiang, Jessica Smith, Emma Mortensen, Peter J. Cook, Karen Sommer, Iram Khan, Denny Liggitt, David J. Rawlings, Jane H. Buckner
Abstract
Adoptive transfer of regulatory T cells (T regs ) is therapeutic in type 1 diabetes (T1D) mouse models. T regs that are specific for pancreatic islets are more potent than polyclonal T regs in preventing disease. However, the frequency of antigen-specific natural T regs is extremely low, and ex vivo expansion may destabilize T regs , leading to an effector phenotype. Here, we generated durable, antigen-specific engineered T regs (EngT regs ) from primary human CD4 + T cells by combining FOXP3 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 regs that suppressed effector T cell (T eff ) proliferation and cytokine production. EngT regs suppressed T effs recognizing the same islet antigen in addition to bystander T effs recognizing other islet antigens through production of soluble mediators and both direct and indirect mechanisms. Adoptively transferred murine islet-specific EngT regs homed to the pancreas and blocked diabetes triggered by islet-specific T effs or diabetogenic polyclonal T effs in recipient mice. These data demonstrate the potential of antigen-specific EngT regs as a targeted therapy for preventing T1D.