PD-1 is a glycoprotein that also resembles CD28, but instead of linking with the B7 (CD80/CD86) molecules, such as CTLA-4, it has specific ligands, namely PD-L1 and PD-L2.15,16 PD-1 can be found on the surface of a number of immune cells, including macrophages, dendritic cells, B cell and T cells.17 Normally the expression of this molecule is low, but it is increased after T-cell activation or more constantly in the case of patients with chronic infections. PD-L2 is primarily expressed on macrophages and dendritic cells, but PD-L1 expression is universal. Indeed, PD-L1 has been found on both immune and nonimmune cells, such as hepatocytes, pancreatic islet cells, endothelial cells, thyroid cells and muscle cells.16,17 Interestingly, various tumor cells can express PD-L1 and this is one of the mechanisms that make such cells capable of escaping the host immune system.18 Connection of PD-1 with one of its ligands induces intracellular biochemical changes that result in decrease of glucose uptake and gluconeogenesis of T cells. This phenomenon exhausts T cells, and the co-stimulatory pathways, such as CD28-CD80/86, are indirectly interrupted.11,12,15

In summary, even though the complete mechanisms of action are complex and remain to be further elucidated, there is a clear role of CTLA-4 and PD-1 as inhibitory ICs that regulate the immune response.