Figure 1. Complex interactions between the CTLA-4/CD28 and PD-1 families of receptors and ligands.
Shown are the defined interactions between the co-inhibitory (checkpoint) receptors, CTLA-4 and PD-1, and their ligands and related receptors. The two known ligands for CTLA-4 are CD80 (B7.1) and CD86 (B7.2). CD86 can “backwards signal” into antigen presenting cells (APCs) when engaged by CTLA-4, inducing the immune inhibitory enzyme indolamine 2’3’ dioxygenase (IDO). CD80 and CD86 also bind the co-stimulatory receptor CD28 on T cells. Recently, another B7 family member, ICOS-L, which was discovered as the ligand for the co-stimulatory receptor ICOS (not shown), was reported to bind to CD28 leading to co-stimulation independent of CD80 or CD86. The two defined ligands for PD-1, namely PD-L1 (B7-H1) and PD-L2 (B7-DC), bind to additional molecules. PD-L1 binds CD80 molecules expressed on activated T cells, mediating inhibition. Additionally, PD-L1 on APCs appears to provide inhibitory signals (“backwards signaling”) when it is engaged by PD-1. PD-L2 binds another molecule, repulsive guidance molecule b (RGMb), which is expressed on macrophages and some epithelial cell types and appears to deliver an inhibitory immune signal through an as yet undefined mechanism. Though not identified, genetic evidence from PD-1 knockout T cells and knockout mice suggests the existence of another receptor for PD-L2 that is co-stimulatory.