CTLA-4
CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is an immune checkpoint receptor that inhibits T-cell activation at the priming stage, when a T cell first encounters an antigen-presenting cell.
Function
CTLA-4 competes with the costimulatory receptor CD28 for the same ligands, CD80 and CD86, on antigen-presenting cells. CD28 binding delivers the second signal a naive T cell needs to activate; CTLA-4 binds CD80/CD86 more avidly, delivers an inhibitory signal instead, and removes the ligands from the surface by trans-endocytosis. The receptor’s job is to set the threshold for starting a response, which is why its loss produces explosive lymphoproliferation: mice and humans without CTLA-4 die of autoimmune tissue destruction within weeks.
In cancer
CTLA-4 limits antitumor T-cell priming, and ipilimumab - the anti-CTLA-4 antibody - was the first checkpoint inhibitor to extend survival in metastatic melanoma (2011), the result for which James Allison shared the 2018 Nobel Prize with Tasuku Honjo (PD-1). CTLA-4 blockade works mainly by expanding the pool of primed antitumor T cells, and its toxicity (immune-mediated colitis, hypophysitis) is broader than PD-1 blockade’s because the checkpoint it releases guards every priming event, with the tumor-specificity coming from combination regimens rather than the drug alone.
Notes
- Human gene symbol: CTLA4; UniProt P16410; 223 amino acids; CD28 receptor family; heterodimeric disulfide-linked dimer.