From the Guidelines
CD80 and CD86 are the ligands that bind to CTLA-4, but to enhance T-cell activation, these ligands should not be bound to CTLA-4, instead, they should bind to CD28, which is a co-stimulatory receptor that enhances T-cell activation.
Mechanism of Action
- CTLA-4 is a negative regulator of T-cell activation, and its interaction with its ligands CD80 and CD86 inhibits T-cell activation 1.
- To enhance T-cell activation, the interaction between CTLA-4 and its ligands should be blocked, allowing CD28 to bind to CD80 and CD86, which enhances T-cell activation.
- Ipilimumab, a monoclonal antibody, binds to CTLA-4, blocking its interaction with CD80 and CD86, and thereby enhancing T-cell activation 1.
Relevance to Immunotherapy
- The mechanism of action of ipilimumab and other immune checkpoint inhibitors, such as nivolumab and pembrolizumab, is to prevent the interaction between immune checkpoints, such as CTLA-4 and PD-1, and their ligands, thereby enhancing T-cell activation and promoting an immune response against cancer cells 1.
From the Research
Ligand/Cofactor Binding to CTLA-4
- The ligands that bind to CTLA-4 are CD80 and CD86, which are also the ligands for CD28 2, 3, 4, 5, 6.
- CD86 is a key target for CTLA-4 immune regulation, and defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity 2.
- CTLA-4 is a disulfide-linked homodimer that binds two CD86 molecules, with each monomeric polypeptide chain containing a high affinity binding site for B7 molecules 3.
- The binding of CD80 and CD86 to CTLA-4 provides a competitive inhibition to CD28-mediated T-cell activation, with CTLA-4 having a stronger affinity for the ligands than CD28 4.
- The interaction between CTLA-4 and its ligands plays a crucial role in regulating T-cell activation, proliferation, and survival, with blockade of CTLA-4-CD80/CD86 interactions reducing T-cell activation and enhancing apoptosis 6.