학술논문
Pancreatic islet-specific engineered Tregsexhibit robust antigen-specific and bystander immune suppression in type 1 diabetes models
Document Type
Article
Author
Yang, Soo Jung; Singh, Akhilesh K.; Drow, Travis; Tappen, Tori; Honaker, Yuchi; Barahmand-pour-Whitman, Fariba; Linsley, Peter S.; Cerosaletti, Karen; Mauk, Kelsey; Xiang, Yufei; Smith, Jessica; Mortensen, Emma; Cook, Peter J.; Sommer, Karen; Khan, Iram; Liggitt, Denny; Rawlings, David J.; Buckner, Jane H.
Source
Science Translational Medicine; October 2022, Vol. 14 Issue: 665
Subject
Language
ISSN
19466234; 19466242
Abstract
Adoptive transfer of regulatory T cells (Tregs) is therapeutic in type 1 diabetes (T1D) mouse models. Tregsthat are specific for pancreatic islets are more potent than polyclonal Tregsin preventing disease. However, the frequency of antigen-specific natural Tregsis extremely low, and ex vivo expansion may destabilize Tregs, leading to an effector phenotype. Here, we generated durable, antigen-specific engineered Tregs(EngTregs) from primary human CD4+T cells by combining FOXP3homology-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 EngTregsthat suppressed effector T cell (Teff) proliferation and cytokine production. EngTregssuppressed Teffsrecognizing the same islet antigen in addition to bystander Teffsrecognizing other islet antigens through production of soluble mediators and both direct and indirect mechanisms. Adoptively transferred murine islet-specific EngTregshomed to the pancreas and blocked diabetes triggered by islet-specific Teffsor diabetogenic polyclonal Teffsin recipient mice. These data demonstrate the potential of antigen-specific EngTregsas a targeted therapy for preventing T1D.