Role of the PD-1/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance for Prevention of Type 1 Diabetes

The human pancreas, like almost all organs in the human body, is immunologically tolerated despite the presence of innate and adaptive immune cells that promptly mediate protective immune responses against pathogensin situ. The PD-1/PD-L1 inhibitory pathway seems to play a key role in the maintenance of immune tolerance systemically and within the pancreatic tissue. Tissue resident memory T cells (TRM), T regulatory cells (Treg), macrophages and even beta cells exhibit PD-1 or PD-L1 expression that contributes in controlling pancreatic immune homeostasis and tolerance. Dysregulation of the PD-1/PD-L1 axis as shown by animal studies and our recent experience with checkpoint inhibitory blockade in humans can lead to immune dysfunctions leading to chronic inflammatory disease and to type 1 diabetes (T1D) in genetically susceptible individuals. In this review, we discuss the role of the PD-1/PD-L1 axis in pancreatic tissue homeostasis and tolerance, speculate how genetic and environmental factors can regulate the PD-1/PD-L1 pathway, and discuss PD-1/PD-L1-based therapeutic approaches for pancreatic islet transplantation and T1D treatment.