Role of the PD-1/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance


Role of the PD-1/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance

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 pathogens in 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 β 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.

Type 1 diabetes (T1D) is an autoimmune disease mediated by T-cell destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans. The critical link between the Programmed death 1 (PD-1)/PD-L1 pathway and constraint of T1D has been demonstrated in numerous studies and has paved the way for novel therapeutic approaches. PD-1 is an inhibitory molecule belonging to the class of co-stimulatory molecules expressed on the surface of T cells that has been linked to immune tolerance. PD-1 is a member of the CD28 and CTLA-4 immunoglobulin superfamily and interacts with two B7 family ligands, PD-L1 (CD274) and PD-L2 (CD273). PD-L1 is widely distributed on leukocytes and non-hematopoietic cells in lymphoid and non-lymphoid tissues, including pancreatic islets, whereas PD-L2 is expressed exclusively on dendritic cells (DCs) and monocytes.


Editorial Assistant
Pancreatic Disorder and Therapy