LAG3 (CD223)

Target id: 2932

Nomenclature: LAG3 (CD223)

Systematic Nomenclature: CD223

Family: Other immune checkpoint proteins, CD molecules

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     LAG3 (CD223) has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 525 12p13.31 LAG3 lymphocyte activating 3 6
Mouse - 521 6 F2 Lag3 lymphocyte-activation gene 3
Rat - 525 4q42 Lag3 lymphocyte activating 3
Gene and Protein Information Comments
The human LAG3 protein precursor is 525 amino acids including its 28 aa signal peptide. LAG3 cleavage to a soluble form is mediated by the metalloproteinases ADAM10 and ADAM17 [2-3], although the biological function of this soluble protein is not fully resolved.
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Affinity Units Reference
BMS-986016 Hs Antagonist - - 4
[4]
Immunopharmacology Comments
LAG3 (CD223) is a T cell inhibitory receptor and immune checkpoint being investigated as a cancer immunotherapeutic target [1], akin to the checkpoints CTLA-4/CD80/86 and PD-1/PD-L1 which have already proven successful in the clinic [5,7]. Understanding novel T-cell inhibitory receptor pathways such as LAG3 could lead to the development of new combinatorial therapeutic approaches in immuno-oncology (see BMS-986016).

Accumulating evidence links LAG3 activity with decreased proliferation and function of Treg cells, and promotion of autoimmunity in chronic autoimmune-prone models, that may contribute to Treg insufficiency in autoimmune diseases such as psoriasis (see NCT02195349- evaluating anti-LAG3 mAb GSK2831781) and type 1 diabetes [8].
Immuno Cell Type Associations
Immuno Cell Type:  Natural killer cells
Cell Ontology Term:   natural killer cell (CL:0000623)
Comment:  LAG3 is expressed on activated human NK cells.
References:  6
Immuno Cell Type:  T cells
Cell Ontology Term:   CD4-positive, alpha-beta T cell (CL:0000624)
CD8-positive, alpha-beta T cell (CL:0000625)
Comment:  LAG3 is an activation marker for CD4+ and CD8+ T cells.
References:  6
Immuno Process Associations
Immuno Process:  Antigen presentation
Immuno Process ID:  3
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886) TAS
References: 
Immuno Process:  Inflammation
Immuno Process ID:  2
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  positive regulation of natural killer cell mediated cytotoxicity (GO:0045954) IEA
References: 
Immuno Process:  T cell (activation)
Immuno Process ID:  4
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  negative regulation of T cell activation (GO:0050868) IEA
References: 
Immuno Process:  Immune regulation
Immuno Process ID:  6
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  positive regulation of natural killer cell mediated cytotoxicity (GO:0045954) IEA
negative regulation of T cell activation (GO:0050868) IEA
References: 
Immuno Process:  Cytokine production & signalling
Immuno Process ID:  9
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  negative regulation of interleukin-2 biosynthetic process (GO:0045085) IEA
References: 
Immuno Process:  Chemotaxis & migration
Immuno Process ID:  10
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  negative regulation of T cell activation (GO:0050868) IEA
References: 
Immuno Process:  Cellular signalling
Immuno Process ID:  11
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  negative regulation of T cell activation (GO:0050868) IEA
References: 
General Comments
Residues in the proline-rich D1 loop of LAG3 facilitate binding to MHC class II molecules. LAG3 probably transmits inhibitory signals via its cytoplasmic domain but the precise signalling mechanism remains unknown. MHC class II expressed by melanoma cells may bind to LAG3 on melanoma-infiltrating T cells and this might facilitate their clonal exhaustion, and enhance tumour cell immune evasion. LAG3 may also interact with galectin-3, a T cell regulating lectin, and this could potentially contribute to LAG3's regulation of CD8+ cell function.

References

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1. Andrews LP, Marciscano AE, Drake CG, Vignali DA. (2017) LAG3 (CD223) as a cancer immunotherapy target. Immunol. Rev.276 (1): 80-96. [PMID:28258692]

2. Clayton KL, Douglas-Vail MB, Nur-ur Rahman AK, Medcalf KE, Xie IY, Chew GM, Tandon R, Lanteri MC, Norris PJ, Deeks SG et al.. (2015) Soluble T cell immunoglobulin mucin domain 3 is shed from CD8+ T cells by the sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression. J. Virol.89 (7): 3723-36. [PMID:25609823]

3. Li N, Workman CJ, Martin SM, Vignali DA. (2004) Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223). J. Immunol.173 (11): 6806-12. [PMID:15557174]

4. Lonberg N, Srinivasan M. (2014) Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof. Patent number: WO2014008218. Assignee: Bristol-Myers Squibb Company. Priority date: 02/07/2012. Publication date: 09/01/2014.

5. Sharpe AH. (2017) Introduction to checkpoint inhibitors and cancer immunotherapy. Immunol. Rev.276 (1): 5-8. [PMID:28258698]

6. Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T. (1990) LAG-3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med.171 (5): 1393-405. [PMID:1692078]

7. Turnis ME, Andrews LP, Vignali DA. (2015) Inhibitory receptors as targets for cancer immunotherapy. Eur. J. Immunol.45 (7): 1892-905. [PMID:26018646]

8. Zhang Q, Chikina M, Szymczak-Workman AL, Horne W, Kolls JK, Vignali KM, Normolle D, Bettini M, Workman CJ, Vignali DAA. (2017) LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes. Sci Immunol2 (9). [PMID:28783703]

How to cite this page

CD molecules: LAG3 (CD223). Last modified on 11/08/2017. Accessed on 18/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2932.