Cell & Stem Cell Research

Allogenic islet transplantation is an important therapeutic approach for the treatment of type 1 diabetes (T1D). However, graft rejection initiated and perpetuated by pathogenic T effector (Teff) cells presents a major barrier. One approach that has proven successful for promoting graft tolerance is shifting the T cell balance away from the induction of pathogenic Teff cells and towards the generation of protective T regulatory (Treg) cells. PD-1/PD-L1 immune checkpoint pathway plays an important role in the Teff and Treg balance with demonstrated clinical efficacy in cancer immunotherapy. We generated a chimeric PD-L1 molecule that can be transiently displayed on the surface of pancreatic islets. In vitro, PD-L1 enhanced TGF-beta-induced conversion of Teff into Treg cells and effectively suppressed the proliferation of Teff cells in response to alloantigen stimulation. In vivo, PD-L1-engineered BALB/c islet grafts under a short window of rapamycin treatment achieved sustained long-term graft survival and function. These results provide strong proof-of-efficacy and feasibility for using PD-L1 protein as an immunomodulator to promote allogeneic islet graft survival in the absence of continued immunosuppression.