CD223 LAG-3 (lymphocyte activation gene 3)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
T Cell
NK Cell
70 / 70

Expression
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.

Structure
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.
 
MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Activated human T and NK cells 70 kDa 70 kDa
Unknown protein 45 kDa 45 kDa CD223 is non-covalently associated with a 45 kDa unknown protein

POST-TRANSCRIPTIONAL MODIFICATION

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. 

POST-TRANSLATIONAL MODIFICATION

There are 4 potential N-glycosylation sites.  An endoglycosydase treatment of the 70 kDa CD223 protein gives a 50 kDa species.


Ligands
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.


Function
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.


Comments
MOLECULAR INTERACTIONS -
PROTEIN AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD223: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD223: No information.

ADDITIONAL INSIGHTS

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
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3902P18627
MouseX98113
Antibodies

Revised June 25, 2008


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