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Wikipedia

Lymphocyte-activation gene 3

August 25, 2023

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene.[5] LAG3, which was discovered in 1990[6] and was designated CD223 (cluster of differentiation 223) after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000,[7] is a cell surface molecule with diverse biologic effects on T cell function. 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.[8]

LAG3
Identifiers
AliasesLAG3, CD223, lymphocyte activating 3
External IDsOMIM: 153337 MGI: 106588 HomoloGene: 1719 GeneCards: LAG3
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
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene Edit

The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4.[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.[9]

Protein Edit

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. 70% homology with murine LAG3.[6] The homology of pig LAG3 is 78%.[10]

Tissue distribution Edit

LAG-3 is expressed on activated T cells,[11] natural killer cells,[6] B cells[12] and plasmacytoid dendritic cells.[13]

Function Edit

LAG3's main ligand is MHC class II, to which it binds with higher affinity than CD4.[14] The protein negatively regulates cellular proliferation, activation,[15] and homeostasis of T cells, in a similar fashion to CTLA-4 and PD-1[16][17] and has been reported to play a role in Treg suppressive function.[18]

Fibrinogen-like protein1 FGL1, a liver-secreted protein, is another (major) LAG3 functional ligand independent of MHC-II.[19]

LAG3 also helps maintain CD8+ T cells in a tolerogenic state[9] and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection.[20]

LAG3 is known to be involved in the maturation and activation of dendritic cells.[21]

Use as a pharmaceutical and as a drug target Edit

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

  • The first is IMP321,[22] a soluble LAG3 which activates dendritic cells.[23]
  • The second are antibodies to LAG3 which take the brakes off the anti-cancer immune response.[8] An example is relatlimab, an anti-LAG3 monoclonal antibody that is currently in phase 2 clinical testing.[24] A number of additional LAG3 antibodies are in preclinical development.[25] LAG-3 may be a better checkpoint inhibitor target than CTLA-4 or PD-1 since antibodies to these two checkpoints only activate effector T cells, and do not inhibit Treg activity, 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.[26] Combination therapies are also ongoing involving LAG-3 antibodies and CTLA-4 or PD-1 antibodies.[8][24]
  • The third are agonist antibodies to LAG3 in order to blunt an autoimmune response. An example of this approach is GSK2831781 which has entered clinical testing (for plaque psoriasis).[27]

History Edit

1990 to 1999 Edit

LAG3 was discovered in 1990 by Frédéric Triebel (currently Chief Scientific Officer at Immutep) when he headed the cellular immunology group in the Department of Clinical Biology at the Institut Gustave Roussy.[28] An initial characterization of the LAG-3 protein was reported in 1992 showing that it was a ligand for MHC class II antigens[29] while a 1995 paper showed that it bound MHC Class II better than CD4.[14] In 1996 INSERM scientists from Strasbourg showed, in knockout mice that were deficient in both CD4 and LAG-3, that the two proteins were not functionally equivalent.[30] The first characterization of the MHC Class II binding sites on LAG-3 were reported by Triebel's group in 1997.[31] The phenotype of LAG-3 knockout mice, as established by the INSERM Strasbourg group in 1996, demonstrated that LAG-3 was vital for the proper functioning of natural killer cells[32] 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.[33]

In May 1996 scientists at the University of Florence showed that CD4+ T cells that were LAG-3+ preferentially expressed IFN-γ, and this was up-regulated by IL-12[34] 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.[35] Subsequent work at the Sapienza University of Rome in 1998 showed that IFN-γ is not required for expression but rather for the up-regulation of LAG-3.[36] The Triebel group in 1998 established that LAG-3 expression on activated human T cells is upregulated by IL-2, IL-7 and IL-12 and also showed that expression of LAG-3 may be controlled by some CD4 regulatory elements.[37] 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.[38] This relationship was confirmed in 1999 with co-capping experiments and with conventional fluorescence microscopy.[39] In 1999 Triebel showed that LAG-3 could be used as a cancer vaccine, through cancer cell lines transfected with LAG-3.[40]

2000 to 2009. Edit

In 2001 the Triebel group identified a LAG3-associated protein, called LAP, that seemed to participate in immune system down-regulation.[41] Also in 2001 the Triebel group reported finding LAG3 expression on CD8+ tumor-infiltrating lymphocytes, with this LAG3 contributing to APC activation.[42] In August 2002 the first phenotypic analysis of the murine LAG-3 was reported by a team at St. Jude Children's Research Hospital in Memphis.[43] 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.[44] In 2003 the Triebel group was able to identify the MHC class II signal transduction pathways in human dendritic cells induced by LAG3.[45] while the St. Jude Children's Research Hospital team showed that the absence of LAG3 caused no defect in T cell function.[16]

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.[17] This was in spite of earlier in vitro work that seemed to suggest that LAG-3 was necessary for T cell expansion.[16] Work at Johns Hopkins University published in October 2004 identified LAG3's key role in regulatory T cells.[18] 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.[46]

In January 2005 scientists at the D'Annunzio University of Chieti–Pescara showed that LAG-3 expression by tumour cells would recruit APCs into the tumour which would have Th1 commitment.[47] Scientists working with AstraZeneca reported in March 2005 that SNPs on LAG3 conferred susceptibility to multiple sclerosis[48] although later work at the Karolinska Institute showed no significant association.[49] 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.[50] In July 2005 scientists at the Institute for Research in Biomedicine in Bellinzona established that LAG3 expression on B cells is induced by T cells[12]

In 2006 scientists at the Istituto Superiore di Sanità in Rome showed that LAG could be used as a biomarker to assess the induction of Th-type responses in recipients of acellular pertussis vaccines.[51]

In April 2007 scientists working at Edward Jenner Institute for Vaccine Research in the UK demonstrated that LAG-3 participates in Treg-induced upregulation of CCR7 and CXCR4 on dendritic cells, resulting in semi-mature dendritic cells with the ability to migrate into lymphoid organs.[52] Scientists at Sun Yat-sen University in China showed that LAG-3 played a role in immune privilege in the eye.[53] 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.[54]

In 2009 the St. Jude Children's Research Hospital group reported that LAG3 appeared on plasmacytoid dendritic cells.[13] Scientists at the University of Tokyo showed that LAG-3 was a marker of Tregs that secrete IL-10.[55]

2010 to 2015. Edit

In 2010 scientists at Swiss Federal Institute of Technology in Zurich showed that LAG3 was an exhaustion marker for CD8+ T cells specific for Lymphocytic choriomeningitis virus, but alone did not significantly contribute to T-cell exhaustion.[56] A team at Roswell Park Comprehensive Cancer Center showed that CD8+ Tumor-infiltrating lymphocytes that were specific for NY-ESO-1 were negatively regulated by LAG-3 and PD-1 in ovarian cancer.[57] 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.[58] Scientists at the Istituto Nazionale dei Tumori in Milan, 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.[59] Geneticists working at the National Cancer Institute reported that SNPs in the LAG3 gene were associated with higher risk of multiple myeloma.[60]

In 2011 scientists studying transplantation biology at Massachusetts General Hospital reported that when antibodies to CD40L induced tolerance in allogeneic bone marrow transplantation, LAG3 was part of the mechanism of action in CD8+ cells.[61] 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.[62] The St. Jude Children's Research Hospital group showed that LAG3 can play a modulating role in autoimmune diabetes.[63] Microbiologists at the University of Iowa demonstrated that blockade of PD-L1 and LAG-3 was a valid therapeutic strategy for Plasmodium infection.[64]

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.[65] Scientists at Hanyang University in Seoul showed that tetravalent CTLA4-Ig and tetravalent LAG3-Ig could synergistically prevent acute graft-versus-host disease in animal models.[66] In 2013 scientists at the San Raffaele Scientific Institute in Milan showed that LAG3 was a marker of type 1 Tregs.[67]

In 2014 scientists at Stanford University showed that LAG engagement could diminish alloreactive T cell responses after bone marrow transplantation.[68] 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.[69] 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.[70] A group at Korea University in Seoul demonstrated that LAG-3 translocates to the cell surface in activated T cells via the cytoplasmic domain through protein kinase C signaling.[71]

In 2015 scientists at the University of Tokyo showed how LAG3 on Tregs work with TGF beta 3 to suppress antibody production.[72] At Tulane University bacteriologists working at the Tulane National Primate Research Center showed in rhesus macaques that Mycobacterium tuberculosis could work through LAG3 to modulate an anti-bacterial immune response.[73] At National Taiwan University a group showed that LAG3 plays a role in the immunosuppressive capability of Tregs stimulated by Peyer's patch B cells.[74]

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Further reading Edit

  • Triebel F (Dec 2003). "LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination". Trends in Immunology. 24 (12): 619–22. doi:10.1016/j.it.2003.10.001. PMID 14644131.
  • Baixeras E, Huard B, Miossec C, Jitsukawa S, Martin M, Hercend T, Auffray C, Triebel F, Piatier-Tonneau D (Aug 1992). "Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens". The Journal of Experimental Medicine. 176 (2): 327–37. doi:10.1084/jem.176.2.327. PMC 2119326. PMID 1380059.
  • Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T (May 1990). "LAG-3, a novel lymphocyte activation gene closely related to CD4". The Journal of Experimental Medicine. 171 (5): 1393–405. doi:10.1084/jem.171.5.1393. PMC 2187904. PMID 1692078.
  • Blum MD, Wong GT, Higgins KM, Sunshine MJ, Lacy E (May 1993). "Reconstitution of the subclass-specific expression of CD4 in thymocytes and peripheral T cells of transgenic mice: identification of a human CD4 enhancer". The Journal of Experimental Medicine. 177 (5): 1343–58. doi:10.1084/jem.177.5.1343. PMC 2191022. PMID 8097522.
  • Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, Maigret B, Dréano M, Triebel F (May 1997). "Characterization of the major histocompatibility complex class II binding site on LAG-3 protein". Proceedings of the National Academy of Sciences of the United States of America. 94 (11): 5744–9. Bibcode:1997PNAS...94.5744H. doi:10.1073/pnas.94.11.5744. PMC 20850. PMID 9159144.
  • Bruniquel D, Borie N, Triebel F (1998). "Genomic organization of the human LAG-3/CD4 locus". Immunogenetics. 47 (1): 96–8. doi:10.1007/s002510050332. PMID 9382927. S2CID 11259106.
  • Bruniquel D, Borie N, Hannier S, Triebel F (Jul 1998). "Regulation of expression of the human lymphocyte activation gene-3 (LAG-3) molecule, a ligand for MHC class II". Immunogenetics. 48 (2): 116–24. doi:10.1007/s002510050411. PMID 9634475. S2CID 24657573.
  • Hannier S, Tournier M, Bismuth G, Triebel F (Oct 1998). "CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling". Journal of Immunology. 161 (8): 4058–65. doi:10.4049/jimmunol.161.8.4058. PMID 9780176. S2CID 21850137.
  • Hannier S, Triebel F (Nov 1999). "The MHC class II ligand lymphocyte activation gene-3 is co-distributed with CD8 and CD3-TCR molecules after their engagement by mAb or peptide-MHC class I complexes". International Immunology. 11 (11): 1745–52. doi:10.1093/intimm/11.11.1745. PMID 10545478.
  • Iouzalen N, Andreae S, Hannier S, Triebel F (Oct 2001). "LAP, a lymphocyte activation gene-3 (LAG-3)-associated protein that binds to a repeated EP motif in the intracellular region of LAG-3, may participate in the down-regulation of the CD3/TCR activation pathway". European Journal of Immunology. 31 (10): 2885–91. doi:10.1002/1521-4141(2001010)31:10<2885::AID-IMMU2885>3.0.CO;2-2. PMID 11592063. S2CID 26417417.
  • Andreae S, Piras F, Burdin N, Triebel F (Apr 2002). "Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223)". Journal of Immunology. 168 (8): 3874–80. doi:10.4049/jimmunol.168.8.3874. PMID 11937541.
  • Andreae S, Buisson S, Triebel F (Sep 2003). "MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223)". Blood. 102 (6): 2130–7. doi:10.1182/blood-2003-01-0273. PMID 12775570.
  • Cai XF, Tao Z, Yan ZQ, Yang SL, Gong Y (Apr 2003). "Molecular cloning, characterisation and tissue-specific expression of human LAG3, a member of the novel Lag1 protein family". DNA Sequence. 14 (2): 79–86. doi:10.1080/1042517021000041831. PMID 12825348. S2CID 35336813.
  • Gandhi MK, Lambley E, Duraiswamy J, Dua U, Smith C, Elliott S, Gill D, Marlton P, Seymour J, Khanna R (Oct 2006). "Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients". Blood. 108 (7): 2280–9. doi:10.1182/blood-2006-04-015164. PMID 16757686.
  • Lundmark F, Harbo HF, Celius EG, Saarela J, Datta P, Oturai A, Lindgren CM, Masterman T, Salter H, Hillert J (Nov 2006). "Association analysis of the LAG3 and CD4 genes in multiple sclerosis in two independent populations". Journal of Neuroimmunology. 180 (1–2): 193–8. doi:10.1016/j.jneuroim.2006.08.009. PMID 17020785. S2CID 13944409.

External links Edit

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

August 25, 2023
lymphocyte, activation, gene, also, known, protein, which, humans, encoded, lag3, gene, lag3, which, discovered, 1990, designated, cd223, cluster, differentiation, after, seventh, human, leucocyte, differentiation, antigen, workshop, 2000, cell, surface, molec. Lymphocyte activation gene 3 also known as LAG 3 is a protein which in humans is encoded by the LAG3 gene 5 LAG3 which was discovered in 1990 6 and was designated CD223 cluster of differentiation 223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000 7 is a cell surface molecule with diverse biologic effects on T cell function 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 8 LAG3IdentifiersAliasesLAG3 CD223 lymphocyte activating 3External IDsOMIM 153337 MGI 106588 HomoloGene 1719 GeneCards LAG3Gene location Human Chr Chromosome 12 human 1 Band12p13 31Start6 772 512 bp 1 End6 778 455 bp 1 Gene location Mouse Chr Chromosome 6 mouse 2 Band6 6 F2Start124 881 324 bp 2 End124 888 668 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inspleenright lobe of liverleft uterine tubelymph nodeappendixgastric mucosaupper lobe of left lungcanal of the cervixrectumsmooth muscle tissueTop expressed inthymuslipsuperior frontal gyrusspleenneural tubeyolk sacesophagusmirrorcerebellar cortexduodenumMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionantigen binding transmembrane signaling receptor activity MHC class II protein bindingCellular componentmembrane external side of plasma membrane integral component of membrane plasma membraneBiological processnegative regulation of T cell activation cell surface receptor signaling pathway positive regulation of natural killer cell mediated cytotoxicity antigen processing and presentation of exogenous peptide antigen via MHC class IISources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez390216768EnsemblENSG00000089692ENSMUSG00000030124UniProtP18627Q61790RefSeq mRNA NM 002286NM 008479RefSeq protein NP 002277NP 032505Location UCSC Chr 12 6 77 6 78 MbChr 6 124 88 124 89 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Gene 2 Protein 3 Tissue distribution 4 Function 5 Use as a pharmaceutical and as a drug target 6 History 6 1 1990 to 1999 6 2 2000 to 2009 6 3 2010 to 2015 7 References 8 Further reading 9 External linksGene EditThe LAG3 gene contains 8 exons The sequence data exon intron organization and chromosomal localization all indicate a close relationship of LAG3 to CD4 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 9 Protein EditThe 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 70 homology with murine LAG3 6 The homology of pig LAG3 is 78 10 Tissue distribution EditLAG 3 is expressed on activated T cells 11 natural killer cells 6 B cells 12 and plasmacytoid dendritic cells 13 Function EditLAG3 s main ligand is MHC class II to which it binds with higher affinity than CD4 14 The protein negatively regulates cellular proliferation activation 15 and homeostasis of T cells in a similar fashion to CTLA 4 and PD 1 16 17 and has been reported to play a role in Treg suppressive function 18 Fibrinogen like protein1 FGL1 a liver secreted protein is another major LAG3 functional ligand independent of MHC II 19 LAG3 also helps maintain CD8 T cells in a tolerogenic state 9 and working with PD 1 helps maintain CD8 exhaustion during chronic viral infection 20 LAG3 is known to be involved in the maturation and activation of dendritic cells 21 Use as a pharmaceutical and as a drug target EditThere are three approaches involving LAG3 that are in clinical development The first is IMP321 22 a soluble LAG3 which activates dendritic cells 23 The second are antibodies to LAG3 which take the brakes off the anti cancer immune response 8 An example is relatlimab an anti LAG3 monoclonal antibody that is currently in phase 2 clinical testing 24 A number of additional LAG3 antibodies are in preclinical development 25 LAG 3 may be a better checkpoint inhibitor target than CTLA 4 or PD 1 since antibodies to these two checkpoints only activate effector T cells and do not inhibit Treg activity 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 26 Combination therapies are also ongoing involving LAG 3 antibodies and CTLA 4 or PD 1 antibodies 8 24 The third are agonist antibodies to LAG3 in order to blunt an autoimmune response An example of this approach is GSK2831781 which has entered clinical testing for plaque psoriasis 27 History Edit1990 to 1999 Edit LAG3 was discovered in 1990 by Frederic Triebel currently Chief Scientific Officer at Immutep when he headed the cellular immunology group in the Department of Clinical Biology at the Institut Gustave Roussy 28 An initial characterization of the LAG 3 protein was reported in 1992 showing that it was a ligand for MHC class II antigens 29 while a 1995 paper showed that it bound MHC Class II better than CD4 14 In 1996 INSERM scientists from Strasbourg showed in knockout mice that were deficient in both CD4 and LAG 3 that the two proteins were not functionally equivalent 30 The first characterization of the MHC Class II binding sites on LAG 3 were reported by Triebel s group in 1997 31 The phenotype of LAG 3 knockout mice as established by the INSERM Strasbourg group in 1996 demonstrated that LAG 3 was vital for the proper functioning of natural killer cells 32 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 33 In May 1996 scientists at the University of Florence showed that CD4 T cells that were LAG 3 preferentially expressed IFN g and this was up regulated by IL 12 34 while in 1997 the same group showed that IFN g production was a driver of LAG 3 expression during the lineage commitment of human naive T cells 35 Subsequent work at the Sapienza University of Rome in 1998 showed that IFN g is not required for expression but rather for the up regulation of LAG 3 36 The Triebel group in 1998 established that LAG 3 expression on activated human T cells is upregulated by IL 2 IL 7 and IL 12 and also showed that expression of LAG 3 may be controlled by some CD4 regulatory elements 37 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 38 This relationship was confirmed in 1999 with co capping experiments and with conventional fluorescence microscopy 39 In 1999 Triebel showed that LAG 3 could be used as a cancer vaccine through cancer cell lines transfected with LAG 3 40 2000 to 2009 Edit In 2001 the Triebel group identified a LAG3 associated protein called LAP that seemed to participate in immune system down regulation 41 Also in 2001 the Triebel group reported finding LAG3 expression on CD8 tumor infiltrating lymphocytes with this LAG3 contributing to APC activation 42 In August 2002 the first phenotypic analysis of the murine LAG 3 was reported by a team at St Jude Children s Research Hospital in Memphis 43 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 44 In 2003 the Triebel group was able to identify the MHC class II signal transduction pathways in human dendritic cells induced by LAG3 45 while the St Jude Children s Research Hospital team showed that the absence of LAG3 caused no defect in T cell function 16 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 17 This was in spite of earlier in vitro work that seemed to suggest that LAG 3 was necessary for T cell expansion 16 Work at Johns Hopkins University published in October 2004 identified LAG3 s key role in regulatory T cells 18 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 46 In January 2005 scientists at the D Annunzio University of Chieti Pescara showed that LAG 3 expression by tumour cells would recruit APCs into the tumour which would have Th1 commitment 47 Scientists working with AstraZeneca reported in March 2005 that SNPs on LAG3 conferred susceptibility to multiple sclerosis 48 although later work at the Karolinska Institute showed no significant association 49 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 50 In July 2005 scientists at the Institute for Research in Biomedicine in Bellinzona established that LAG3 expression on B cells is induced by T cells 12 In 2006 scientists at the Istituto Superiore di Sanita in Rome showed that LAG could be used as a biomarker to assess the induction of Th type responses in recipients of acellular pertussis vaccines 51 In April 2007 scientists working at Edward Jenner Institute for Vaccine Research in the UK demonstrated that LAG 3 participates in Treg induced upregulation of CCR7 and CXCR4 on dendritic cells resulting in semi mature dendritic cells with the ability to migrate into lymphoid organs 52 Scientists at Sun Yat sen University in China showed that LAG 3 played a role in immune privilege in the eye 53 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 54 In 2009 the St Jude Children s Research Hospital group reported that LAG3 appeared on plasmacytoid dendritic cells 13 Scientists at the University of Tokyo showed that LAG 3 was a marker of Tregs that secrete IL 10 55 2010 to 2015 Edit In 2010 scientists at Swiss Federal Institute of Technology in Zurich showed that LAG3 was an exhaustion marker for CD8 T cells specific for Lymphocytic choriomeningitis virus but alone did not significantly contribute to T cell exhaustion 56 A team at Roswell Park Comprehensive Cancer Center showed that CD8 Tumor infiltrating lymphocytes that were specific for NY ESO 1 were negatively regulated by LAG 3 and PD 1 in ovarian cancer 57 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 58 Scientists at the Istituto Nazionale dei Tumori in Milan 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 59 Geneticists working at the National Cancer Institute reported that SNPs in the LAG3 gene were associated with higher risk of multiple myeloma 60 In 2011 scientists studying transplantation biology at Massachusetts General Hospital reported that when antibodies to CD40L induced tolerance in allogeneic bone marrow transplantation LAG3 was part of the mechanism of action in CD8 cells 61 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 62 The St Jude Children s Research Hospital group showed that LAG3 can play a modulating role in autoimmune diabetes 63 Microbiologists at the University of Iowa demonstrated that blockade of PD L1 and LAG 3 was a valid therapeutic strategy for Plasmodium infection 64 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 65 Scientists at Hanyang University in Seoul showed that tetravalent CTLA4 Ig and tetravalent LAG3 Ig could synergistically prevent acute graft versus host disease in animal models 66 In 2013 scientists at the San Raffaele Scientific Institute in Milan showed that LAG3 was a marker of type 1 Tregs 67 In 2014 scientists at Stanford University showed that LAG engagement could diminish alloreactive T cell responses after bone marrow transplantation 68 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 69 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 70 A group at Korea University in Seoul demonstrated that LAG 3 translocates to the cell surface in activated T cells via the cytoplasmic domain through protein kinase C signaling 71 In 2015 scientists at the University of Tokyo showed how LAG3 on Tregs work with TGF beta 3 to suppress antibody production 72 At Tulane University bacteriologists working at the Tulane National Primate Research Center showed in rhesus macaques that Mycobacterium tuberculosis could work through LAG3 to modulate an anti bacterial immune response 73 At National Taiwan University a group showed that LAG3 plays a role in the immunosuppressive capability of Tregs stimulated by Peyer s patch B cells 74 References Edit a b c GRCh38 Ensembl release 89 ENSG00000089692 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000030124 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine a b Entrez Gene LAG3 lymphocyte activation gene 3 a b c Triebel F Jitsukawa S Baixeras E Roman Roman S Genevee C Viegas Pequignot E Hercend T May 1990 LAG 3 a novel lymphocyte activation gene closely related to CD4 The Journal of Experimental Medicine 171 5 1393 405 doi 10 1084 jem 171 5 1393 PMC 2187904 PMID 1692078 Mason D Andre P Bensussan A Buckley C Civin C Clark E de Haas M Goyert S Hadam M Hart D Horejsi V Meuer S Morrissey J Schwartz Albiez R Shaw S Simmons D Uguccioni M van der Schoot E Vivier E Zola H Nov 2001 CD antigens 2001 Journal of Leukocyte Biology 70 5 685 90 doi 10 1189 jlb 70 5 685 PMID 11698486 S2CID 33478518 a b c Syn Nicholas L Teng Michele W L Mok Tony S K Soo Ross A December 2017 De novo and acquired resistance to immune checkpoint targeting The Lancet Oncology 18 12 e731 e741 doi 10 1016 s1470 2045 17 30607 1 PMID 29208439 a b Grosso JF Kelleher CC Harris TJ Maris CH Hipkiss EL De Marzo A Anders R Netto G Getnet D Bruno TC Goldberg MV Pardoll DM Drake CG Nov 2007 LAG 3 regulates CD8 T cell accumulation and effector function in murine self and tumor tolerance systems The Journal of Clinical Investigation 117 11 3383 92 doi 10 1172 JCI31184 PMC 2000807 PMID 17932562 Kim SS Kim SH Kang HS Chung HY Choi I Cheon YP Lee KH Lee DM Park J Lee SY Chun T Jan 2010 Molecular cloning and expression analysis of pig lymphocyte activation gene 3 LAG 3 CD223 Veterinary Immunology and Immunopathology 133 1 72 9 doi 10 1016 j vetimm 2009 07 001 PMID 19631993 Huard B Gaulard P Faure F Hercend T 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Ji L Sun J Chen L Chen Y Zhu G Yin W Zheng L Zhou T Badri T Yao S Zhu S Boto A Sznol M Melero I Vignali DA Schalper K Chen L Jan 2019 Fibrinogen like Protein 1 Is a Major Immune Inhibitory Ligand of LAG 3 Cell 176 1 2 334 47 doi 10 1016 j cell 2018 11 010 PMC 6365968 PMID 30580966 Blackburn SD Shin H Haining WN Zou T Workman CJ Polley A Betts MR Freeman GJ Vignali DA Wherry EJ Jan 2009 Coregulation of CD8 T cell exhaustion by multiple inhibitory receptors during chronic viral infection Nature Immunology 10 1 29 37 doi 10 1038 ni 1679 PMC 2605166 PMID 19043418 Andreae S Piras F Burdin N Triebel F Apr 2002 Maturation and activation of dendritic cells induced by lymphocyte activation gene 3 CD223 Journal of Immunology 168 8 3874 80 doi 10 4049 jimmunol 168 8 3874 PMID 11937541 Oncology Pipeline at Immutep Immunotherapy Treatment www immutep com Retrieved 2019 12 09 Avice M Sarfati M Triebel F Delespesse G Demeure CE March 1 1999 Lymphocyte activation gene 3 a MHC class II ligand expressed on activated T cells stimulates TNF alpha and IL 12 production by monocytes and dendritic cells J Immunol 162 5 2748 53 doi 10 4049 jimmunol 162 5 2748 PMID 10072520 S2CID 24564488 a b Clinical trial number NCT03704077 for An Investigational Immuno therapy Study of Relatlimab Plus Nivolumab Compared to Various Standard of Care Therapies in Previously Treated Participants With Recurrent Advanced or Metastatic Gastric Cancer or Gastroesophageal Junction Adenocarcinoma at ClinicalTrials gov Tesaro s Immuno Oncology Platform Tesaro web site Technology Platforms Immutep LAG 3 Archived from the original on 1 July 2015 Retrieved 1 July 2015 A First in Human Study to Evaluate the Safety Tolerability Pharmacokinetics and Pharmacodynamics of a Intravenous IV Dose of GSK2831781 in Healthy Subjects and Patients With Plaque Psoriasis Triebel F Jitsukawa S Baixeras E Roman Roman S Genevee C Viegas Pequignot E Hercend T May 1990 LAG 3 a novel lymphocyte activation gene closely related to CD4 The Journal of Experimental Medicine 171 5 1393 405 doi 10 1084 jem 171 5 1393 PMC 2187904 PMID 1692078 Baixeras E Huard B Miossec C Jitsukawa S Martin M Hercend T Auffray C Triebel F Piatier Tonneau D Aug 1992 Characterization of the lymphocyte activation gene 3 encoded protein A new ligand for human leukocyte antigen class II antigens The Journal of Experimental Medicine 176 2 327 37 doi 10 1084 jem 176 2 327 PMC 2119326 PMID 1380059 Miyazaki T Dierich A Benoist C Mathis D May 1996 LAG 3 is not responsible for selecting T helper cells in CD4 deficient mice International Immunology 8 5 725 9 doi 10 1093 intimm 8 5 725 PMID 8671660 Huard B Mastrangeli R Prigent P Bruniquel D Donini S El Tayar N Maigret B Dreano M Triebel F May 1997 Characterization of the major histocompatibility complex class II binding site on LAG 3 protein Proceedings of the National Academy of Sciences of the United States of America 94 11 5744 9 Bibcode 1997PNAS 94 5744H doi 10 1073 pnas 94 11 5744 PMC 20850 PMID 9159144 Miyazaki T Dierich A Benoist C Mathis D Apr 1996 Independent modes of natural killing distinguished in mice lacking Lag3 Science 272 5260 405 8 Bibcode 1996Sci 272 405M doi 10 1126 science 272 5260 405 PMID 8602528 S2CID 30676426 Huard B Tournier M Triebel F Apr 1998 LAG 3 does not define a specific mode of natural killing in human Immunology Letters 61 2 3 109 12 doi 10 1016 s0165 2478 97 00170 3 PMID 9657262 Annunziato F Manetti R Tomasevic I Guidizi MG Biagiotti R Gianno V Germano P Mavilia C Maggi E Romagnani S May 1996 Expression and release of LAG 3 encoded protein by human CD4 T cells are associated with IFN gamma production FASEB Journal 10 7 769 76 doi 10 1096 fasebj 10 7 8635694 PMID 8635694 S2CID 5807706 Annunziato F Manetti R Cosmi L Galli G Heusser CH Romagnani S Maggi E Sep 1997 Opposite role for interleukin 4 and interferon gamma on CD30 and lymphocyte activation gene 3 LAG 3 expression by activated naive T cells European Journal of Immunology 27 9 2239 44 doi 10 1002 eji 1830270918 PMID 9341765 S2CID 35524015 Scala E Carbonari M Del Porto P Cibati M Tedesco T Mazzone AM Paganelli R Fiorilli M Jul 1998 Lymphocyte activation gene 3 LAG 3 expression and IFN gamma production are variably coregulated in different human T lymphocyte subpopulations Journal of Immunology 161 1 489 93 doi 10 4049 jimmunol 161 1 489 PMID 9647260 S2CID 23898756 Bruniquel D Borie N Hannier S Triebel F Jul 1998 Regulation of expression of the human lymphocyte activation gene 3 LAG 3 molecule a ligand for MHC class II Immunogenetics 48 2 116 24 doi 10 1007 s002510050411 PMID 9634475 S2CID 24657573 Hannier S Tournier M Bismuth G Triebel F Oct 1998 CD3 TCR complex associated lymphocyte activation gene 3 molecules inhibit CD3 TCR signaling Journal of Immunology 161 8 4058 65 doi 10 4049 jimmunol 161 8 4058 PMID 9780176 S2CID 21850137 Hannier S Triebel F Nov 1999 The MHC class II ligand lymphocyte activation gene 3 is co distributed with CD8 and CD3 TCR molecules after their engagement by mAb or peptide MHC class I complexes International Immunology 11 11 1745 52 doi 10 1093 intimm 11 11 1745 PMID 10545478 Prigent P El Mir S Dreano M Triebel F Dec 1999 Lymphocyte activation gene 3 induces tumor regression and antitumor immune responses European Journal of Immunology 29 12 3867 76 doi 10 1002 SICI 1521 4141 199912 29 12 lt 3867 AID IMMU3867 gt 3 0 CO 2 E PMID 10601994 Iouzalen N Andreae S Hannier S Triebel F Oct 2001 LAP a lymphocyte activation gene 3 LAG 3 associated protein that binds to a repeated EP motif in the intracellular region of LAG 3 may participate in the down regulation of the CD3 TCR activation pathway European Journal of Immunology 31 10 2885 91 doi 10 1002 1521 4141 2001010 31 10 lt 2885 AID IMMU2885 gt 3 0 CO 2 2 PMID 11592063 S2CID 26417417 Demeure CE Wolfers J Martin Garcia N Gaulard P Triebel F Sep 2001 T Lymphocytes infiltrating various tumour types express the MHC class II ligand lymphocyte activation gene 3 LAG 3 role of LAG 3 MHC 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6806 12 doi 10 4049 jimmunol 173 11 6806 PMID 15557174 Di Carlo E Cappello P Sorrentino C D Antuono T Pellicciotta A Giovarelli M Forni G Musiani P Triebel F Jan 2005 Immunological mechanisms elicited at the tumour site by lymphocyte activation gene 3 LAG 3 versus IL 12 sharing a common Th1 anti tumour immune pathway The Journal of Pathology 205 1 82 91 doi 10 1002 path 1679 PMID 15586367 S2CID 25569191 Zhang Z Duvefelt K Svensson F Masterman T Jonasdottir G Salter H Emahazion T Hellgren D Falk G Olsson T Hillert J Anvret M Mar 2005 Two genes encoding immune regulatory molecules LAG3 and IL7R confer susceptibility to multiple sclerosis Genes and Immunity 6 2 145 52 doi 10 1038 sj gene 6364171 PMID 15674389 Lundmark F Harbo HF Celius EG Saarela J Datta P Oturai A Lindgren CM Masterman T Salter H Hillert J Nov 2006 Association analysis of the LAG3 and CD4 genes in multiple sclerosis in two independent populations Journal of Neuroimmunology 180 1 2 193 8 doi 10 1016 j jneuroim 2006 08 009 PMID 17020785 S2CID 13944409 Macon Lemaitre L Triebel F Jun 2005 The negative regulatory function of the lymphocyte activation gene 3 co receptor CD223 on human T cells Immunology 115 2 170 8 doi 10 1111 j 1365 2567 2005 02145 x PMC 1782137 PMID 15885122 Ausiello CM Palazzo R Spensieri F Urbani F Massari M Triebel F Benagiano M D Elios MM Del Prete G Cassone A January 1 2006 Soluble CD30 and lymphocyte activation gene 3 CD223 as potential serological markers of T helper type cytokine response induced by acellular pertussis vaccine International Journal of Immunopathology and Pharmacology 19 1 97 104 doi 10 1177 205873920601900109 hdl 11365 1220733 PMID 16569347 Bayry J Triebel F Kaveri SV Tough DF Apr 2007 Human dendritic cells acquire a semimature phenotype and lymph node homing potential through interaction with CD4 CD25 regulatory T cells Journal of Immunology 178 7 4184 93 doi 10 4049 jimmunol 178 7 4184 PMID 17371975 Zhu X Yang P Zhou H Li B Huang X Meng Q Wang L Kijlstra A Oct 2007 CD4 CD25 Tregs express an increased LAG 3 and CTLA 4 in anterior chamber associated immune deviation Graefe s Archive for Clinical and Experimental Ophthalmology Albrecht von Graefes Archiv fur Klinische und Experimentelle Ophthalmologie 245 10 1549 57 doi 10 1007 s00417 007 0591 8 PMID 17541623 S2CID 23556661 Grosso JF Kelleher CC Harris TJ Maris CH Hipkiss EL De Marzo A Anders R Netto G Getnet D Bruno TC Goldberg MV Pardoll DM Drake CG Nov 2007 LAG 3 regulates CD8 T cell accumulation and effector function in murine self and tumor tolerance systems The Journal of Clinical Investigation 117 11 3383 92 doi 10 1172 JCI31184 PMC 2000807 PMID 17932562 Okamura T Fujio K Shibuya M Sumitomo S Shoda H Sakaguchi S Yamamoto K Aug 2009 CD4 CD25 LAG3 regulatory T cells controlled by the transcription factor Egr 2 Proceedings of the National Academy of Sciences of the United States of America 106 33 13974 9 Bibcode 2009PNAS 10613974O doi 10 1073 pnas 0906872106 PMC 2729005 PMID 19666526 Richter K Agnellini P Oxenius A Jan 2010 On the role of the inhibitory receptor LAG 3 in acute and chronic LCMV infection International Immunology 22 1 13 23 doi 10 1093 intimm dxp107 PMID 19880580 Matsuzaki J Gnjatic S Mhawech Fauceglia P Beck A Miller A Tsuji T Eppolito C Qian F Lele S Shrikant P Old LJ Odunsi K Apr 2010 Tumor infiltrating NY ESO 1 specific CD8 T cells are negatively regulated by LAG 3 and PD 1 in human ovarian cancer Proceedings of the National Academy of Sciences of the United States of America 107 17 7875 80 Bibcode 2010PNAS 107 7875M doi 10 1073 pnas 1003345107 PMC 2867907 PMID 20385810 Woo SR Li N Bruno TC Forbes K Brown S Workman C Drake CG Vignali DA Jun 2010 Differential subcellular localization of the regulatory T cell protein LAG 3 and the coreceptor CD4 European Journal of Immunology 40 6 1768 77 doi 10 1002 eji 200939874 PMC 2987677 PMID 20391435 Camisaschi C Casati C Rini F Perego M De Filippo A Triebel F Parmiani G Belli F Rivoltini L Castelli C Jun 2010 LAG 3 expression defines a subset of CD4 CD25 high Foxp3 regulatory T cells that are expanded at tumor sites Journal of Immunology 184 11 6545 51 doi 10 4049 jimmunol 0903879 PMID 20421648 Lee KM Baris D Zhang Y Hosgood HD Menashe I Yeager M Zahm SH Wang SS Purdue MP Chanock S Zheng T Rothman N Lan Q Aug 2010 Common single nucleotide polymorphisms in immunoregulatory genes and multiple myeloma risk among women in Connecticut American Journal of Hematology 85 8 560 3 doi 10 1002 ajh 21760 PMC 2910184 PMID 20568250 Lucas CL Workman CJ Beyaz S LoCascio S Zhao G Vignali DA Sykes M May 2011 LAG 3 TGF b and cell intrinsic PD 1 inhibitory pathways contribute to CD8 but not CD4 T cell tolerance induced by allogeneic BMT with anti CD40L Blood 117 20 5532 40 doi 10 1182 blood 2010 11 318675 PMC 3109721 PMID 21422469 Hemon P Jean Louis F Ramgolam K Brignone C Viguier M Bachelez H Triebel F Charron D Aoudjit F Al Daccak R Michel L May 2011 MHC class II engagement by its ligand LAG 3 CD223 contributes to melanoma resistance to apoptosis Journal of Immunology 186 9 5173 83 doi 10 4049 jimmunol 1002050 PMID 21441454 Bettini M Szymczak Workman AL Forbes K Castellaw AH Selby M Pan X Drake CG Korman AJ Vignali DA Oct 2011 Cutting edge accelerated autoimmune diabetes in the absence of LAG 3 Journal of Immunology 187 7 3493 8 doi 10 4049 jimmunol 1100714 PMC 3178660 PMID 21873518 Butler NS Moebius J Pewe LL Traore B Doumbo OK Tygrett LT Waldschmidt TJ Crompton PD Harty JT Feb 2012 Therapeutic blockade of PD L1 and LAG 3 rapidly clears established blood stage Plasmodium infection Nature Immunology 13 2 188 95 doi 10 1038 ni 2180 PMC 3262959 PMID 22157630 Woo SR Turnis ME Goldberg MV Bankoti J Selby M Nirschl CJ Bettini ML Gravano DM Vogel P Liu CL Tangsombatvisit S Grosso JF Netto G Smeltzer MP Chaux A Utz PJ Workman CJ Pardoll DM Korman AJ Drake CG Vignali DA Feb 2012 Immune inhibitory molecules LAG 3 and PD 1 synergistically regulate T cell function to promote tumoral immune escape Cancer Research 72 4 917 27 doi 10 1158 0008 5472 CAN 11 1620 PMC 3288154 PMID 22186141 Cho H Chung YH Aug 2012 Construction and in vitro and in vivo analyses of tetravalent immunoadhesins Journal of Microbiology and Biotechnology 22 8 1066 76 doi 10 4014 jmb 1201 01026 PMID 22713982 Gagliani N Magnani CF Huber S Gianolini ME Pala M Licona Limon P Guo B Herbert DR Bulfone A Trentini F Di Serio C Bacchetta R Andreani M Brockmann L Gregori S Flavell RA Roncarolo MG Jun 2013 Coexpression of CD49b and LAG 3 identifies human and mouse T regulatory type 1 cells Nature Medicine 19 6 739 46 doi 10 1038 nm 3179 PMID 23624599 S2CID 21305032 Sega EI Leveson Gower DB Florek M Schneidawind D Luong RH Negrin RS January 27 2014 Role of lymphocyte activation gene 3 Lag 3 in conventional and regulatory T cell function in allogeneic transplantation PLOS ONE 9 1 e86551 Bibcode 2014PLoSO 986551S doi 10 1371 journal pone 0086551 PMC 3903521 PMID 24475140 Pena J Jones NG Bousheri S Bangsberg DR Cao H Jun 2014 Lymphocyte activation gene 3 expression defines a discrete subset of HIV specific CD8 T cells that is associated with lower viral load AIDS Research and Human Retroviruses 30 6 535 41 doi 10 1089 AID 2012 0195 PMC 4046223 PMID 24180338 Camisaschi C De Filippo A Beretta V Vergani B Villa A Vergani E Santinami M Cabras AD Arienti F Triebel F Rodolfo M Rivoltini L Castelli C Jul 2014 Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions involvement of LAG 3 The Journal of Investigative Dermatology 134 7 1893 902 doi 10 1038 jid 2014 29 PMID 24441096 Bae J Lee SJ Park CG Lee YS Chun T Sep 2014 Trafficking of LAG 3 to the surface on activated T cells via its cytoplasmic domain and protein kinase C signaling Journal of Immunology 193 6 3101 12 doi 10 4049 jimmunol 1401025 PMID 25108024 Okamura T Sumitomo S Morita K Iwasaki Y Inoue M Nakachi S Komai T Shoda H Miyazaki J Fujio K Yamamoto K February 19 2015 TGF b3 expressing CD4 CD25 LAG3 regulatory T cells control humoral immune responses Nature Communications 6 6329 6329 Bibcode 2015NatCo 6 6329O doi 10 1038 ncomms7329 PMC 4346620 PMID 25695838 Phillips BL Mehra S Ahsan MH Selman M Khader SA Kaushal D Mar 2015 LAG3 expression in active Mycobacterium tuberculosis infections The American Journal of Pathology 185 3 820 33 doi 10 1016 j ajpath 2014 11 003 PMC 4348466 PMID 25549835 Chu KH Chiang BL May 2015 Characterization and functional studies of forkhead box protein 3 lymphocyte activation gene 3 CD4 regulatory T cells induced by mucosal B cells Clinical and Experimental Immunology 180 2 316 28 doi 10 1111 cei 12583 PMC 4408166 PMID 25581421 Further reading EditTriebel F Dec 2003 LAG 3 a regulator of T cell and DC responses and its use in therapeutic vaccination Trends in Immunology 24 12 619 22 doi 10 1016 j it 2003 10 001 PMID 14644131 Baixeras E Huard B Miossec C Jitsukawa S Martin M Hercend T Auffray C Triebel F Piatier Tonneau D Aug 1992 Characterization of the lymphocyte activation gene 3 encoded protein A new ligand for human leukocyte antigen class II antigens The Journal of Experimental Medicine 176 2 327 37 doi 10 1084 jem 176 2 327 PMC 2119326 PMID 1380059 Triebel F Jitsukawa S Baixeras E Roman Roman S Genevee C Viegas Pequignot E Hercend T May 1990 LAG 3 a novel lymphocyte activation gene closely related to CD4 The Journal of Experimental Medicine 171 5 1393 405 doi 10 1084 jem 171 5 1393 PMC 2187904 PMID 1692078 Blum MD Wong GT Higgins KM Sunshine MJ Lacy E May 1993 Reconstitution of the subclass specific expression of CD4 in thymocytes and peripheral T cells of transgenic mice identification of a human CD4 enhancer The Journal of Experimental Medicine 177 5 1343 58 doi 10 1084 jem 177 5 1343 PMC 2191022 PMID 8097522 Huard B Mastrangeli R Prigent P Bruniquel D Donini S El Tayar N Maigret B Dreano M Triebel F May 1997 Characterization of the major histocompatibility complex class II binding site on LAG 3 protein Proceedings of the National Academy of Sciences of the United States of America 94 11 5744 9 Bibcode 1997PNAS 94 5744H doi 10 1073 pnas 94 11 5744 PMC 20850 PMID 9159144 Bruniquel D Borie N Triebel F 1998 Genomic organization of the human LAG 3 CD4 locus Immunogenetics 47 1 96 8 doi 10 1007 s002510050332 PMID 9382927 S2CID 11259106 Bruniquel D Borie N Hannier S Triebel F Jul 1998 Regulation of expression of the human lymphocyte activation gene 3 LAG 3 molecule a ligand for MHC class II Immunogenetics 48 2 116 24 doi 10 1007 s002510050411 PMID 9634475 S2CID 24657573 Hannier S Tournier M Bismuth G Triebel F Oct 1998 CD3 TCR complex associated lymphocyte activation gene 3 molecules inhibit CD3 TCR signaling Journal of Immunology 161 8 4058 65 doi 10 4049 jimmunol 161 8 4058 PMID 9780176 S2CID 21850137 Hannier S Triebel F Nov 1999 The MHC class II ligand lymphocyte activation gene 3 is co distributed with CD8 and CD3 TCR molecules after their engagement by mAb or peptide MHC class I complexes International Immunology 11 11 1745 52 doi 10 1093 intimm 11 11 1745 PMID 10545478 Iouzalen N Andreae S Hannier S Triebel F Oct 2001 LAP a lymphocyte activation gene 3 LAG 3 associated protein that binds to a repeated EP motif in the intracellular region of LAG 3 may participate in the down regulation of the CD3 TCR activation pathway European Journal of Immunology 31 10 2885 91 doi 10 1002 1521 4141 2001010 31 10 lt 2885 AID IMMU2885 gt 3 0 CO 2 2 PMID 11592063 S2CID 26417417 Andreae S Piras F Burdin N Triebel F Apr 2002 Maturation and activation of dendritic cells induced by lymphocyte activation gene 3 CD223 Journal of Immunology 168 8 3874 80 doi 10 4049 jimmunol 168 8 3874 PMID 11937541 Andreae S Buisson S Triebel F Sep 2003 MHC class II signal transduction in human dendritic cells induced by a natural ligand the LAG 3 protein CD223 Blood 102 6 2130 7 doi 10 1182 blood 2003 01 0273 PMID 12775570 Cai XF Tao Z Yan ZQ Yang SL Gong Y Apr 2003 Molecular cloning characterisation and tissue specific expression of human LAG3 a member of the novel Lag1 protein family DNA Sequence 14 2 79 86 doi 10 1080 1042517021000041831 PMID 12825348 S2CID 35336813 Gandhi MK Lambley E Duraiswamy J Dua U Smith C Elliott S Gill D Marlton P Seymour J Khanna R Oct 2006 Expression of LAG 3 by tumor infiltrating lymphocytes is coincident with the suppression of latent membrane antigen specific CD8 T cell function in Hodgkin lymphoma patients Blood 108 7 2280 9 doi 10 1182 blood 2006 04 015164 PMID 16757686 Lundmark F Harbo HF Celius EG Saarela J Datta P Oturai A Lindgren CM Masterman T Salter H Hillert J Nov 2006 Association analysis of the LAG3 and CD4 genes in multiple sclerosis in two independent populations Journal of Neuroimmunology 180 1 2 193 8 doi 10 1016 j jneuroim 2006 08 009 PMID 17020785 S2CID 13944409 External links EditLAG3 protein human at the U S National Library of Medicine Medical Subject Headings MeSH LAG 3 Identification amp Validation Of Next Generation Checkpoint Pathway by Frederic Triebel March 22 2018This article incorporates text from the United States National Library of Medicine which is in the public domain Retrieved from https en wikipedia org w index php title Lymphocyte activation gene 3 amp oldid 1171928975, wikipedia, wiki, book, books, library,

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