| Primary Identifier | IPR008096 | Type | Family |
| Short Name | CTLA4 |
| description | T cell-dependent immune processes require cell-surface interactions thatmediate the initiation, modulation and the ultimate course of the response.The specificity of T cell recognition is determined by the engagement of theT cell receptor (TCR) on T cells with cognate peptide-MHC complexes presented by antigen presenting cells (APCs). Additional signals arerequired to sustain and enhance T cell activity, the most important of whichis 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 isoformswith cytotoxic T lymphocyte-associated molecule-4 CTLA-4, a CD28 homologue receptor on T cells (31% identity), provides inhibitory signals requiredfor down-regulation of the response, while it may also prevent T cell activation by weak TCR signals[, , , , ].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, Tcell activation leads to both increased CTLA4 gene expression andtrafficking of CTLA4 protein to the cell surface. In addition, CTLA-4exhibits an affinity for the B7 isoforms that is 10 to 100 times that forCD28. Covalent dimerisation of CTLA4 is required for its high bindingavidity, but each monomeric subunit also contains a binding site for CD80and CD86. It is likely that CTLA-4 directly competes with CD28 for bindingB7 and also directs the assembly of inhibitory signalling complexes thatlead to quiescence or anergy. Thus the balance between the opposing signals elicited by CD28 and CTLA-4 is central to the regulation of T cellresponsiveness and homeostasis. One mechanism by which CTLA-4 may performthis function is by regulating cell-cycle progression; by contrast with CD28, which down-regulates the cell-cycle inhibitor p27kip1, CTLA-4 prevents this degradation[, , ].Sequence comparison between human CTLA-4 and CD28 proteins suggests they arehomologous, with the highest of degree of similarity being in the juxta-membrane and cytoplasmic regions. In addition, the cytoplasmic domainsof human and murine CTLA-4 are identical, suggesting that this region hasimportant functional properties [].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 circumstancesto block or reverse this effect. |
