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Lymphocyte-activation gene 3

(Redirected fromLAG3)

Lymphocyte-activation gene 3,also known asLAG-3,is aproteinwhich in humans is encoded by theLAG3gene.[5]LAG3, which was discovered in 1990[6]and was designatedCD223(cluster of differentiation223) after the SeventhHuman Leucocyte Differentiation Antigen Workshopin 2000,[7]is a cell surface molecule with diverse biological effects onT cellfunction but overall has an immune inhibitory effect. It is animmune checkpointreceptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer andautoimmunedisorders. In soluble form it is also being developed as a cancer drug in its own right.[8]

LAG3
Identifiers
AliasesLAG3,CD223, lymphocyte activating 3
External IDsOMIM:153337;MGI:106588;HomoloGene:1719;GeneCards:LAG3;OMA:LAG3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3902

16768

Ensembl

ENSG00000089692

ENSMUSG00000030124

UniProt

P18627

Q61790

RefSeq (mRNA)

NM_002286

NM_008479

RefSeq (protein)

NP_002277

NP_032505

Location (UCSC)Chr 12: 6.77 – 6.78 MbChr 6: 124.88 – 124.89 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Conservation of their respective cytoplasmic tail motifs, CxC/H in the case of CD4 and an ITIM-like motif in the case of LAG-3, supports that competition between CD4 and LAG-3 for binding of kinase LCK is a conserved core part of the jawed vertebrate immune system.

LAG-3 is closely related to CD4,[9]with which it shares the ability to bind MHC class II molecules.[10]Although there has been conflicting information on which motifs in the LAG-3 cytoplasmic tail are important for function,[11][12][13]evolutionary conversation patterns[14][15]combined with functional studies[12][13]imply that the evolutionarily conserved core function of LAG-3 is aninhibitory competitionthrough animmunoreceptor tyrosine-based inhibitory motif(ITIM)–like motif with the activating receptors CD4 or CD8 for binding the kinaseLCK.[14]

Gene

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TheLAG3gene contains 8exons.The sequence data, exon/intronorganization, and chromosomal localization all indicate a close relationship of LAG3 toCD4.[5]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,[16]and this gene organization can already be found in sharks.

Protein

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The LAG3 protein, which belongs toimmunoglobulin(Ig) superfamily, comprises a 503-amino acidtype I transmembrane proteinwith four extracellular Ig-like domains, designated D1 to D4. When human LAG-3 was cloned in 1990 it was found to have approx. 70% homology with murine LAG3.[6]The homology of pig LAG3 is 78%.[17]

Tissue distribution

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LAG-3 is expressed onactivated T cells,[18]natural killer cells,[6]B cells[19]andplasmacytoid dendritic cells.[20]

Function

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LAG3's main ligand isMHC class II,to which it binds with higher affinity than CD4.[10]The protein negatively regulates cellular proliferation, activation,[21]and homeostasis of T cells, in a similar fashion toCTLA-4andPD-1[22][23]and has been reported to play a role inTregsuppressive function.[24]

Fibrinogen-like protein1FGL1,a liver-secreted protein, is another (major) LAG3 functional ligand independent of MHC-II.[25]

LAG3 also helps maintainCD8+T cells in a tolerogenic state[16]and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection.[26]

LAG3 is known to be involved in the maturation and activation ofdendritic cells.[27]

Use as a pharmaceutical and as a drug target

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There are three approaches involving LAG3 that are in clinical development.

  • The first isIMP321,[28]a soluble LAG3 which activatesdendritic cells.[29]
  • The second are antibodies to LAG3 which take the brakes off the anti-cancer immune response.[8]An example isrelatlimab,an anti-LAG3 monoclonal antibody that is currently in phase 2 clinical testing.[30]A number of additional LAG3 antibodies are in preclinical development.[31]LAG-3 may be a bettercheckpoint inhibitortarget thanCTLA-4orPD-1since antibodies to these two checkpoints only activate effector T cells, and do not inhibitTregactivity, whereas an antagonist LAG-3 antibody can both activate T effector cells (by downregulating the LAG-3 inhibiting signal into pre-activated LAG-3+ cells) and inhibit induced (i.e. antigen-specific) Treg suppressive activity.[32]Combination therapies are also ongoing involving LAG-3 antibodies and CTLA-4 or PD-1 antibodies.[8][30]
  • The third are agonist antibodies to LAG3 in order to blunt an autoimmune response. An example of this approach isGSK2831781which has entered clinical testing (forplaque psoriasis).[33]

History

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1990 to 1999

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LAG3 was discovered in 1990 byFrédéric Triebel(currently Chief Scientific Officer atImmutep) when he headed the cellular immunology group in the Department of Clinical Biology at theInstitut Gustave Roussy.[9]An initial characterization of the LAG-3 protein was reported in 1992 showing that it was a ligand for MHC class II antigens[34]while a 1995 paper showed that it bound MHC Class II better than CD4.[10]In 1996INSERMscientists fromStrasbourgshowed, inknockout micethat were deficient in both CD4 and LAG-3, that the two proteins were not functionally equivalent.[35]The first characterization of the MHC Class II binding sites on LAG-3 were reported by Triebel's group in 1997.[36]The phenotype of LAG-3knockout mice,as established by the INSERM Strasbourg group in 1996, demonstrated that LAG-3 was vital for the proper functioning ofnatural killer cells[37]but in 1998 Triebel, working with LAG-3 antibodies and soluble protein, found that LAG-3 did not define a specific mode of natural killing.[38]

In May 1996 scientists at theUniversity of Florenceshowed that CD4+T cells that were LAG-3+preferentially expressedIFN-γ,and this was up-regulated byIL-12[39]while in 1997 the same group showed that IFN-γ production was a driver of LAG-3 expression during the lineage commitment of human naive T cells.[40]Subsequent work at theSapienza University of Romein 1998 showed that IFN-γ is not required for expression but rather for the up-regulation of LAG-3.[41]The Triebel group in 1998 established that LAG-3 expression on activated human T cells is upregulated byIL-2,IL-7and IL-12 and also showed that expression of LAG-3 may be controlled by some CD4 regulatory elements.[42]In 1998 the Triebel group showed that, on T cells, LAG-3 down-modulates their proliferation and activation when LAG-3/MHC Class II co-caps with CD3/TCR complex.[43]This relationship was confirmed in 1999 with co-capping experiments and with conventional fluorescence microscopy.[44]In 1999 Triebel showed that LAG-3 could be used as a cancer vaccine, through cancer cell lines transfected with LAG-3.[45]

2000 to 2009.

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In 2001 the Triebel group identified a LAG3-associated protein, called LAP, that seemed to participate in immune system down-regulation.[46]Also in 2001 the Triebel group reported finding LAG3 expression on CD8+tumor-infiltrating lymphocytes,with this LAG3 contributing to APC activation.[47]In August 2002 the first phenotypic analysis of the murine LAG-3 was reported by a team atSt. Jude Children's Research HospitalinMemphis.[48]Molecular analysis reported by the St. Jude Children's Research Hospital team in November 2002 demonstrated that the inhibitory function of LAG-3 is performed via the protein's cytoplasmic domain.[11]In 2003 the Triebel group was able to identify the MHC class II signal transduction pathways in human dendritic cells induced by LAG3.[49]while the St. Jude Children's Research Hospital team showed that the absence of LAG3 caused no defect in T cell function.[22]

In May 2004 the St. Jude Children's Research Hospital team showed, through LAG3 knockout mice, that LAG-3 negatively regulates T cell expansion and controls the size of the memory T cell pool.[23]This was in spite of earlierin vitrowork that seemed to suggest that LAG-3 was necessary for T cell expansion.[22]Work atJohns Hopkins Universitypublished in October 2004 identified LAG3's key role in regulatory T cells.[24]The St. Jude Children's Research Hospital team reported in December 2004 that LAG-3 is cleaved within the D4 transmembrane domain into two fragments that remain membrane-associated: a 54-kDa fragment that contains all the extracellular domains and oligomerizes with full-length LAG-3 (70 kDa) on the cell surface via the D1 domain, and a 16-kDa peptide that contains the transmembrane and cytoplasmic domains and is subsequently released as soluble LAG-3.[50]

In January 2005 scientists at theD'Annunzio University of Chieti–Pescarashowed that LAG-3 expression by tumour cells would recruit APCs into the tumour which would have Th1 commitment.[51]Scientists working withAstraZenecareported in March 2005 that SNPs on LAG3 conferred susceptibility tomultiple sclerosis[52]although later work at theKarolinska Instituteshowed no significant association.[53]In June 2005 the Triebel group showed that antibodies to LAG-3 would result in T cell expansion, through increased rounds of cell division which LAG-3 signalling would otherwise block.[54]In July 2005 scientists at the Institute for Research in Biomedicine inBellinzonaestablished that LAG3 expression on B cells is induced by T cells[19]

In 2006 scientists at theIstituto Superiore di SanitàinRomeshowed that LAG could be used as a biomarker to assess the induction of Th-type responses in recipients of acellularpertussisvaccines.[55]

In April 2007 scientists working atEdward Jenner Institute for Vaccine Researchin the UK demonstrated that LAG-3 participates inTreg-induced upregulation ofCCR7andCXCR4on dendritic cells, resulting in semi-mature dendritic cells with the ability to migrate into lymphoid organs.[56]Scientists atSun Yat-sen Universityin China showed that LAG-3 played a role inimmune privilegein the eye.[57]In late 2007 the St. Jude Children's Research Hospital group showed that LAG-3 maintained tolerance to self and tumor antigens not just via CD4+ cells but also via CD8+ cells, independently of LAG-3's role on TReg cells.[58]

In 2009 the St. Jude Children's Research Hospital group reported that LAG3 appeared on plasmacytoid dendritic cells.[20]Scientists at theUniversity of Tokyoshowed that LAG-3 was a marker of Tregs that secrete IL-10.[59]

2010 to 2015.

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In 2010 scientists atSwiss Federal Institute of Technology in Zurichshowed that LAG3 was an exhaustion marker for CD8+ T cells specific forLymphocytic choriomeningitisvirus, but alone did not significantly contribute to T-cell exhaustion.[60]A team atRoswell Park Comprehensive Cancer Centershowed that CD8+Tumor-infiltrating lymphocytesthat were specific for NY-ESO-1 were negatively regulated by LAG-3 and PD-1 in ovarian cancer.[61]The St. Jude Children's Research Hospital group reported that most LAG3 was housed intracellularly in multiple domains before rapid translocation to the cell surface potentially facilitated by the microtubule organizing center and recycling endosomes during T-cell activation.[62]Scientists at the Istituto Nazionale dei Tumori inMilan,collaborating with the Triebel group, showed that LAG3 defines a potent regulatory T cell subset that shows up more frequently in cancer patients and is expanded at tumor sites.[63]Geneticists working at theNational Cancer Institutereported thatSNPsin the LAG3 gene were associated with higher risk ofmultiple myeloma.[64]

In 2011 scientists studying transplantation biology atMassachusetts General Hospitalreported that when antibodies to CD40L induced tolerance in allogeneic bone marrow transplantation, LAG3 was part of the mechanism of action in CD8+ cells.[65]Scientists at INSERM, working with the Triebel group, showed that the binding of MHC class II molecules on melanoma cells to LAG3 would increase resistance to apoptosis, providing evidence that antibodies to LAG3 would be relevant in melanoma.[66]The St. Jude Children's Research Hospital group showed that LAG3 can play a modulating role in autoimmune diabetes.[67]Microbiologists at theUniversity of Iowademonstrated that blockade of PD-L1 and LAG-3 was a valid therapeutic strategy forPlasmodiuminfection.[68]

In 2012 the St. Jude Children's Research Hospital group showed that LAG-3 and PD-1 synergistically regulate T-cell function in such a way as to allow an anti-tumoral immune response to be blunted.[69]Scientists atHanyang Universityin Seoul showed that tetravalent CTLA4-Ig and tetravalent LAG3-Ig could synergistically prevent acutegraft-versus-host diseasein animal models.[70]In 2013 scientists at the San Raffaele Scientific Institute in Milan showed that LAG3 was a marker of type 1 Tregs.[71]

In 2014 scientists atStanford Universityshowed that LAG engagement could diminish alloreactive T cell responses afterbone marrow transplantation.[72]A group from the California Department of Public Health identified a subset of HIV-specific LAG3(+)CD8(+) T cells that negatively correlated with plasma viral load.[73]The Istituto Nazionale dei Tumori group, collaborating with Triebel, found LAG3 expression on plasmacytoid dendritic cells is in part responsible for directing an immune-suppressive environment.[74]A group atKorea Universityin Seoul demonstrated that LAG-3 translocates to the cell surface in activated T cells via the cytoplasmic domain throughprotein kinase Csignaling.[75]

In 2015 scientists at theUniversity of Tokyoshowed how LAG3 on Tregs work withTGF beta 3to suppress antibody production.[76]AtTulane Universitybacteriologists working at the Tulane National Primate Research Center showed inrhesus macaquesthatMycobacterium tuberculosiscould work through LAG3 to modulate an anti-bacterial immune response.[77]At National Taiwan University a group showed that LAG3 plays a role in the immunosuppressive capability of Tregs stimulated byPeyer's patchB cells.[78]

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