|CD223||LAG-3 (lymphocyte activation gene 3)|
|Molecule Type||Antigen Expression||Molecular Weight|
Min / Max
|Non-lineage Restricted Molecule|
Type 1 glycoprotein
|70 / 70|
|CD223 is expressed on all subsets of T and NK cells following cellular activation but is not expressed in other cell types such as activated B cells or monocytes. Staining reveals cells scattered in germinal centers and T cell areas of lymphoid organs but not in nonlymphoid tissue. On cultured IL-2-dependent T cells, expression of lymphocyte activated gene 3 (LAG-3) is 7-fold higher on CD8+ cells than CD4+ cells. The best cytokine combination to induce CD223 is IL-2+ IL-12.|
|MOLECULAR FAMILY NAME: Belongs to the immunoglobulin supergene family.|
CD223 is a single-pass type-1 498 aa glycoprotein. It contains an extracellular domain which contains an 140 aa N-terminal Ig-like V-type domain (D1) which includes a 30 aa extra loop followed by 3 Ig-like C2-type domains (D2-D4), a transmembrane domain and a short intracellular cytoplasmic domain with a potential serine phosphorylation site and a conserved KIEELE motif and a EP motif at the C-terminus that binds LAG-3 associated protein (LAP). D1 binds a nonpolymorphic region of MHC class II molecules and is required for LAG-3 dimerization. The extra loop in the NH2-terminal D1 Ig domain is part of the MHC class II binding region and an unusual disulfide bond is proposed between stands B and G (not F) in this domain. The CD223 gene contains 8 exons. Based on sequence similarities and intron/exon organization CD223 is likely to have shared an immediate ancestor in evolution and a close relationship with CD4. The CD4 and CD223 genes are closely linked.
Allternatively splicing yields 3 different isoforms. LAG-3V1, (D1-D2 soluble), is 36 kDa. LAG-3V2, (D1-D3 membrane bound) is 61 kDa. LAG-3V3, (D1-D3 soluble), is 52 kDa. There are 3 mRNA with slightly different 5' start sites by spurious transcription.
There are 4 potential N-glycosylation sites. An endoglycosydase treatment of the 70 kDa CD223 protein gives a 50 kDa species.
|LIGANDS AND MOLECULES ASSOCIATED WITH CD223|
CD223 binds MHC class II molecules with a high affinity in a cell rosetting assay. Binding is inhibited by LAG-3 mAbs and by LAG-3 Ig. A 45 kDa protein is coprecipitated with LAG-3 from activated T cells under reducing and non-reducing conditions.
|CD223 is involved in lymphocyte activation and binds to HLA class II antigens. CD223 bind MHC class III and regulates the homeostatic expansion of T cells in vivo. It associates with the TCR-CD3 complex and negatively regulates TCR-mediated signal transduction. This function is mediated via cytoplasmic KIEELE motif. It may help to downregulate TCR signaling which leads to cell inactivation and has a role in downregulating an antigen-specific response which is suggested by the effects of LAG-3 mAbs or LAG-3-Ig in prolonging an antigen-specific immune response by a MHC Class II-restricted CD4+ T cell line. In contrast to its negative regulatory effects, LAG-3 induced MHC class II signaling in monocytes and dendritic cells leads to activation of the antigen-presenting cell and induction of cytotoxic T cells and CD4 Th1 responses in mice coadministered soluble LAG-3 and antigen. CD223 may also help activate CD4 and CD8 T cells to fully activate monocytes and dendritic cells leading to the optimized MHC class I and class II T cell responses. Sequence date indicate a close relationship between CD223 and CD4. LAG-3-deficient mice show normal immune responses, but as mice age, they have increased T-cell numbers compared with wild-type mice. These deficient-mice display normal MHC Class II-restricted responses. Crossing CD223-deficient mice with CD4-deficient mice has revealed that CD223 does not substitute for CD4. .|
BIOCHEMICAL ACTIVITY: No information.
DISEASE RELEVANCE AND FUNCTION OF CD223 IN INTACT ANIMAL
CD223 knockout mice date propose that CD223 defines a specific mode of natural killing, but no evidence that CD223 may be involved in the transducing activity important for NK cell cytotoxicity as has been found in human.
|MOLECULAR INTERACTIONS -|
PROTEIN AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD223: No information.
SUBSTRATES: No information.
ENZYMES WHICH MODIFY CD223: No information.
The role of CD223/MHC class II interactions in vivo is not clearly established. These interactions may complement CD49L/CD40 interactions in T and dendritic cells cross-talk in conditions where CD40L/CD40 interactions are suboptimal. For example the lack of CD40L expression is poorly activated on CD4 cells or on CD8 cells. Th 1 Ag-specific responses in vivo are induced when a soluble CD223 molecule is used as a vaccine adjuvant.
Database accession numbers
Revised June 25, 2008