Cytotoxic T-lymphocyte antigen 4 (IPR008096)

Short name: CTLA4

Overlapping homologous superfamilies

Family relationships


T cell-dependent immune processes require cell-surface interactions that mediate the initiation, modulation and the ultimate course of the response. The specificity of T cell recognition is determined by the engagement of the T cell receptor (TCR) on T cells with cognate peptide-MHC complexes presented by antigen presenting cells (APCs). Additional signals are required to sustain and enhance T cell activity, the most important of which is provided by the engagement of CD28 on T cells with its ligands B7-1 (CD80) and B7-2 (CD86). By contrast, the interaction of B7 isoforms with cytotoxic T lymphocyte-associated molecule-4 CTLA-4, a CD28 homologue receptor on T cells (31% identity), provides inhibitory signals required for down-regulation of the response, while it may also prevent T cell activation by weak TCR signals [PMID: 1714933, PMID: 9600957, PMID: 11052947, PMID: 11841692, PMID: 11807776].

Unlike CD28, which is not expressed on resting T cells, CTLA-4 is not detected on the cell surface until 24 hours after activation. In fact, T cell activation leads to both increased CTLA4 gene expression and trafficking of CTLA4 protein to the cell surface. In addition, CTLA-4 exhibits an affinity for the B7 isoforms that is 10 to 100 times that for CD28. Covalent dimerisation of CTLA4 is required for its high binding avidity, but each monomeric subunit also contains a binding site for CD80 and CD86. It is likely that CTLA-4 directly competes with CD28 for binding B7 and also directs the assembly of inhibitory signalling complexes that lead to quiescence or anergy. Thus the balance between the opposing signals elicited by CD28 and CTLA-4 is central to the regulation of T cell responsiveness and homeostasis. One mechanism by which CTLA-4 may perform this function is by regulating cell-cycle progression; by contrast with CD28, which down-regulates the cell-cycle inhibitor p27kip1, CTLA-4 prevents this degradation [PMID: 9600957, PMID: 11052947, PMID: 11807776].

Sequence comparison between human CTLA-4 and CD28 proteins suggests they are homologous, with the highest of degree of similarity being in the juxta- membrane and cytoplasmic regions. In addition, the cytoplasmic domains of human and murine CTLA-4 are identical, suggesting that this region has important functional properties [PMID: 1714933].

Typically, activation of T cells by TCR-engaging peptide-MHC is dramatically enhanced by interaction of the CD28 co-stimulatory receptor with its ligands CD80 (B7-1) and CD86 (B7-2) on the APC surface. Interestingly, CTLA-4 is transported from intracellular stores toward the region of the cell surface receiving activation signals. This suggests that binding of CD28 to its ligand may occur primarily at the centre of the mature immunological synapse, and that CTLA-4 may be transported to this site under certain circumstances to block or reverse this effect.

GO terms

Biological Process

GO:0006955 immune response

Molecular Function

No terms assigned in this category.

Cellular Component

GO:0016020 membrane

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.