Figure 1.

CTLA-4 or cytotoxic T-lymphocyte-associated antigen 4 is a protein found on T cells that downregulate the immune response. CTLA-4 and PD-1 negatively regulate T-cell activation. CD28 mediates TCR and MHCII complex attachment. CTLA-4 acts as a competitive homolog to CD28 and binds to CD80/CD86, ligands for CD28, thereby preventing T-cell activation. PD-1 binding to PD-L1 also negatively regulates T-cell activation. Both pathways are activated by the activation of TCR. The phosphatase Src homology region-2 containing protein tyrosine phosphatase (SHP-2) is recruited and inhibits PI3K-A downstream signaling. CTLA-4 also reacts with serine/threonine phosphatase PP2A which dephosphorylates AKT and contributes to further inhibition of T-cell activation. CTLA-4 also blocks TCR induction of ZAP-70 micro-cluster formation. Tumor hypoxia-induced HIF-1-alpha stabilization upregulates the expression of CTLA-4, LAG-3, and PD-L1. Figure created in BioRender.

MHCII, major histocompatibility antigen; TCR, T-cell receptor.