LAG3
Description
The LAG3 (lymphocyte activating 3) is a protein-coding gene located on chromosome 12.
Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 (cluster of differentiation 223) after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.
LAG-3 is closely related to CD4, with which it shares the ability to bind MHC class II molecules. Although there has been conflicting information on which motifs in the LAG-3 cytoplasmic tail are important for function, evolutionary conversation patterns combined with functional studies imply that the evolutionarily conserved core function of LAG-3 is an inhibitory competition through an immunoreceptor tyrosine-based inhibitory motif (ITIM)–like motif with the activating receptors CD4 or CD8 for binding the kinase LCK.
== Gene == The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4. The gene for LAG-3 lies adjacent to the gene for CD4 on human chromosome 12 (12p13) and is approximately 20% identical to the CD4 gene, and this gene organization can already be found in sharks.
== Protein == The LAG3 protein, which belongs to immunoglobulin (Ig) superfamily, comprises a 503-amino acid type I transmembrane protein with four extracellular Ig-like domains, designated D1 to D4. When human LAG-3 was cloned in 1990 it was found to have approx.
LAG3 is an inhibitory receptor expressed on activated T cells (PubMed:7805750, PubMed:8647185, PubMed:20421648). It delivers inhibitory signals upon binding to ligands, such as FGL1 (By similarity). FGL1 is a major ligand of LAG3 and is responsible for LAG3's T-cell inhibitory function (By similarity). Following TCR engagement, LAG3 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (By similarity). LAG3 may inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1, possibly by acting as a coreceptor for PDCD1/PD-1 (By similarity). LAG3 negatively regulates the proliferation, activation, effector function, and homeostasis of both CD8(+) and CD4(+) T-cells (PubMed:7805750, PubMed:8647185, PubMed:20421648). It also mediates immune tolerance: it is constitutively expressed on a subset of regulatory T-cells (Tregs) and contributes to their suppressive function (By similarity). LAG3 also acts as a negative regulator of plasmacytoid dendritic cell (pDCs) activation (By similarity). LAG3 binds MHC class II (MHC-II), but the precise role of MHC-II binding is unclear (PubMed:8647185). {ECO:0000250|UniProtKB:Q61790, ECO:0000269|PubMed:20421648, ECO:0000269|PubMed:7805750, ECO:0000269|PubMed:8647185}
LAG3 is also known as CD223.
