Type 1 Diabetes an Autoimmune Disease Mediated by T-cell Destruction

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.

Up on binding to ligands PD-L1 and PD-L2, PD-1 recruits SHP2 phosphatase, which then dephosphorylates molecules downstream of the TCR and CD28, leading to a block in T cell effector function. Thus, PD-1 blockade can reinvigorate exhausted T cells, providing enhanced antiviral and antitumor responses. These observations have led to the development of PD-1 immune checkpoint inhibitors (ICI), which have revolutionized cancer therapy. Interestingly, adverse events such as rapid autoimmunity including T1D developed following checkpoint blockade in cancer patients, possibly due to reversal of T cell exhaustion in pancreatic islets. Those findings suggested a key role for the PD1-PD-L1 inhibitory pathway in the maintenance of immune homeostasis and tolerance in pancreatic tissue and the prevention of T1D. Here, we discuss the role of PD-1 in pancreas immune homeostasis and tolerance and the progress made so far in exploiting the PD-1/PD-L1 dyad as a means to prevent and/or treat T1D.

Regards

John
Editorial Assistant
Pancreatic Disorder and Therapy