LAG3: Difference between revisions

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{{Infobox_gene}}
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'''Lymphocyte-activation gene 3''', also known as '''LAG-3''', is a [[protein]] which in humans is encoded by the ''LAG3'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: LAG3 lymphocyte-activation gene 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3902| accessdate = }}</ref> LAG3, which was discovered in 1990<ref name="Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T 1393–405">{{cite journal | vauthors = Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T | title = LAG-3, a novel lymphocyte activation gene closely related to CD4 | journal = The Journal of Experimental Medicine | volume = 171 | issue = 5 | pages = 1393–405 | date = May 1990 | pmid = 1692078 | doi =  10.1084/jem.171.5.1393 | pmc=2187904}}</ref> and was designated '''CD223''' ([[cluster of differentiation]] 223) after the Seventh [[Cluster of differentiation#Human Leukocyte Differentiation Antigen Workshops|Human Leucocyte Differentiation Antigen Workshop]] in 2000,<ref>{{cite journal | vauthors = Mason D, André P, Bensussan A, Buckley C, Civin C, Clark E, de Haas M, Goyert S, Hadam M, Hart D, Horejsí V, Meuer S, Morrissey J, Schwartz-Albiez R, Shaw S, Simmons D, Uguccioni M, van der Schoot E, Vivier E, Zola H | title = CD antigens 2001 | journal = Journal of Leukocyte Biology | volume = 70 | issue = 5 | pages = 685–90 | date = Nov 2001 | pmid = 11698486 | doi = }}</ref> 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.
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== Gene ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Lymphocyte-activation gene 3
| HGNCid = 6476
| Symbol = LAG3
| AltSymbols =; CD223
| OMIM = 153337
| ECnumber = 
| Homologene = 1719
| MGIid = 106588
| GeneAtlas_image1 = PBB_GE_LAG3_206486_at_tn.png
| Function = {{GNF_GO|id=GO:0003823 |text = antigen binding}} {{GNF_GO|id=GO:0004888 |text = transmembrane receptor activity}} {{GNF_GO|id=GO:0042289 |text = MHC class II protein binding}}
| Component = {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0009897 |text = external side of plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0007166 |text = cell surface receptor linked signal transduction}} {{GNF_GO|id=GO:0045085 |text = negative regulation of interleukin-2 biosynthetic process}} {{GNF_GO|id=GO:0045954 |text = positive regulation of natural killer cell mediated cytotoxicity}} {{GNF_GO|id=GO:0050868 |text = negative regulation of T cell activation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3902
    | Hs_Ensembl = ENSG00000089692
    | Hs_RefseqProtein = NP_002277
    | Hs_RefseqmRNA = NM_002286
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 6751931
    | Hs_GenLoc_end = 6757880
    | Hs_Uniprot = P18627
    | Mm_EntrezGene = 16768
    | Mm_Ensembl = ENSMUSG00000030124
    | Mm_RefseqmRNA = XM_981508
    | Mm_RefseqProtein = XP_986602
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 6
    | Mm_GenLoc_start = 124869980
    | Mm_GenLoc_end = 124877324
    | Mm_Uniprot = Q61790
  }}
}}
'''Lymphocyte-activation gene 3''', also known as '''LAG3''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: LAG3 lymphocyte-activation gene 3| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3902| accessdate = }}</ref> LAG3 has also recently been designated '''CD223''' ([[cluster of differentiation]] 223).


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
The LAG3 gene contains 8 [[exon]]s. The sequence data, exon/[[intron]] organization, and chromosomal localization all indicate a close relationship of LAG3 to [[CD4]].<ref name="entrez" /> 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<ref name="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. 3383–92">{{cite journal | vauthors = 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 | title = LAG-3 regulates CD8<sup>+</sup> T cell accumulation and effector function in murine self- and tumor-tolerance systems | journal = The Journal of Clinical Investigation | volume = 117 | issue = 11 | pages = 3383–92 | date = Nov 2007 | pmid = 17932562 | doi = 10.1172/JCI31184 | pmc=2000807}}</ref>
{{PBB_Summary
| section_title =
| summary_text = Lymphocyte-activation protein 3 belongs to Ig superfamily and contains 4 extracellular Ig-like domains. The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4.<ref name="entrez">{{cite web | title = Entrez Gene: LAG3 lymphocyte-activation gene 3| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3902| accessdate = }}</ref>
}}


==References==
== Protein ==
{{reflist|2}}
The LAG3 protein, which belongs to [[immunoglobulin superfamily|immunoglobulin]] (Ig) superfamily, comprises a 503-[[amino acid]] [[Transmembrane protein#Classification by topology|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.<ref name="Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T 1393–405"/> The homology of pig LAG3 is 78%.<ref>{{cite journal | vauthors = Kim SS, Kim SH, Kang HS, Chung HY, Choi I, Cheon YP, Lee KH, Lee DM, Park J, Lee SY, Chun T | title = Molecular cloning and expression analysis of pig lymphocyte activation gene-3 (LAG-3; CD223) | journal = Veterinary Immunology and Immunopathology | volume = 133 | issue = 1 | pages = 72–9 | date = Jan 2010 | pmid = 19631993 | doi = 10.1016/j.vetimm.2009.07.001 }}</ref>


==Further reading==
== Tissue distribution ==
{{refbegin | 2}}
 
{{PBB_Further_reading
LAG-3 is expressed on [[T cell activation|activated T cell]]s,<ref>{{cite journal | vauthors = Huard B, Gaulard P, Faure F, Hercend T, Triebel F | title = Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand | journal = Immunogenetics | volume = 39 | issue = 3 | pages = 213–7 | date = January 1, 1994 | pmid = 7506235 | doi =  10.1007/bf00241263| url = https://link.springer.com/article/10.1007%2FBF00241263 }}</ref> [[natural killer cells]],<ref name="Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T 1393–405"/> [[B cells]]<ref name="ReferenceA">{{cite journal | vauthors = Kisielow M, Kisielow J, Capoferri-Sollami G, Karjalainen K | title = Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells | journal = European Journal of Immunology | volume = 35 | issue = 7 | pages = 2081–8 | date = Jul 2005 | pmid = 15971272 | doi = 10.1002/eji.200526090 }}</ref> and [[plasmacytoid dendritic cells]].<ref name="ReferenceB">{{cite journal | vauthors = Workman CJ, Wang Y, El Kasmi KC, Pardoll DM, Murray PJ, Drake CG, Vignali DA | title = LAG-3 regulates plasmacytoid dendritic cell homeostasis | journal = Journal of Immunology | volume = 182 | issue = 4 | pages = 1885–91 | date = Feb 2009 | pmid = 19201841 | doi = 10.4049/jimmunol.0800185 | pmc=2675170}}</ref>
| citations =
 
*{{cite journal | author=Triebel F |title=LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination. |journal=Trends Immunol. |volume=24 |issue= 12 |pages= 619-22 |year= 2004 |pmid= 14644131 |doi=  }}
== Function ==
*{{cite journal  | author=Baixeras E, Huard B, Miossec C, ''et al.'' |title=Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. |journal=J. Exp. Med. |volume=176 |issue= 2 |pages= 327-37 |year= 1992 |pmid= 1380059 |doi= }}
 
*{{cite journal | author=Triebel F, Jitsukawa S, Baixeras E, ''et al.'' |title=LAG-3, a novel lymphocyte activation gene closely related to CD4. |journal=J. Exp. Med. |volume=171 |issue= 5 |pages= 1393-405 |year= 1990 |pmid= 1692078 |doi= }}
LAG3's main ligand is [[MHC class II]], to which it binds with higher affinity than CD4.<ref name="Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F. 2718–21">{{cite journal | vauthors = Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F | title = CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins | journal = European Journal of Immunology | volume = 25 | issue = 9 | pages = 2718–21 | date = Sep 1995 | pmid = 7589152 | doi = 10.1002/eji.1830250949 }}</ref> The protein negatively regulates cellular proliferation, activation, and homeostasis of T cells, in a similar fashion to [[CTLA-4]] and [[Programmed cell death 1|PD-1]]<ref name="Workman CJ, Vignali DA. :970–9">{{cite journal | vauthors = Workman CJ, Vignali DA | title = The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells | journal = European Journal of Immunology | volume = 33 | issue = 4 | pages = 970–9 | date = Apr 2003 | pmid = 12672063 | doi = 10.1002/eji.200323382 }}</ref><ref name="Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA 5450–5">{{cite journal | vauthors = Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA | title = Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo | journal = Journal of Immunology | volume = 172 | issue = 9 | pages = 5450–5 | date = May 2004 | pmid = 15100286 | doi =  10.4049/jimmunol.172.9.5450}}</ref> and has been reported to play a role in [[Treg]] suppressive function.<ref name="Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA 503–13">{{cite journal | vauthors = Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA | title = Role of LAG-3 in regulatory T cells | journal = Immunity | volume = 21 | issue = 4 | pages = 503–13 | date = Oct 2004 | pmid = 15485628 | doi = 10.1016/j.immuni.2004.08.010 }}</ref>
*{{cite journal | author=Blum MD, Wong GT, Higgins KM, ''et al.'' |title=Reconstitution of the subclass-specific expression of CD4 in thymocytes and peripheral T cells of transgenic mice: identification of a human CD4 enhancer. |journal=J. Exp. Med. |volume=177 |issue= 5 |pages= 1343-58 |year= 1993 |pmid= 8097522 |doi= }}
 
*{{cite journal | author=Huard B, Mastrangeli R, Prigent P, ''et al.'' |title=Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 11 |pages= 5744-9 |year= 1997 |pmid= 9159144 |doi= }}
LAG3 also helps maintain [[CD8]]<sup>+</sup> T cells in a tolerogenic state<ref name="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. 3383–92"/> and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection.<ref>{{cite journal | vauthors = Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DA, Wherry EJ | title = Coregulation of CD8<sup>+</sup> T cell exhaustion by multiple inhibitory receptors during chronic viral infection | journal = Nature Immunology | volume = 10 | issue = 1 | pages = 29–37 | date = Jan 2009 | pmid = 19043418 | doi = 10.1038/ni.1679 | pmc=2605166}}</ref>
*{{cite journal | author=Bruniquel D, Borie N, Triebel F |title=Genomic organization of the human LAG-3/CD4 locus. |journal=Immunogenetics |volume=47 |issue= 1 |pages= 96-8 |year= 1998 |pmid= 9382927 |doi=  }}
 
*{{cite journal  | author=Bruniquel D, Borie N, Hannier S, Triebel F |title=Regulation of expression of the human lymphocyte activation gene-3 (LAG-3) molecule, a ligand for MHC class II. |journal=Immunogenetics |volume=48 |issue= 2 |pages= 116-24 |year= 1998 |pmid= 9634475 |doi= }}
LAG3 is known to be involved in the maturation and activation of [[dendritic cell]]s.<ref>{{cite journal | vauthors = Andreae S, Piras F, Burdin N, Triebel F | title = Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223) | journal = Journal of Immunology | volume = 168 | issue = 8 | pages = 3874–80 | date = Apr 2002 | pmid = 11937541 | doi =  10.4049/jimmunol.168.8.3874}}</ref>
*{{cite journal  | author=Hannier S, Tournier M, Bismuth G, Triebel F |title=CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling. |journal=J. Immunol. |volume=161 |issue= 8 |pages= 4058-65 |year= 1998 |pmid= 9780176 |doi= }}
 
*{{cite journal | author=Hannier S, Triebel F |title=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. |journal=Int. Immunol. |volume=11 |issue= 11 |pages= 1745-52 |year= 1999 |pmid= 10545478 |doi=  }}
== Use as a pharmaceutical and as a drug target ==
*{{cite journal  | author=Iouzalen N, Andreae S, Hannier S, Triebel F |title=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. |journal=Eur. J. Immunol. |volume=31 |issue= 10 |pages= 2885-91 |year= 2001 |pmid= 11592063 |doi= }}
 
*{{cite journal  | author=Andreae S, Piras F, Burdin N, Triebel F |title=Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223). |journal=J. Immunol. |volume=168 |issue= 8 |pages= 3874-80 |year= 2002 |pmid= 11937541 |doi=  }}
There are three approaches involving LAG3 that are in clinical development.
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
 
*{{cite journal  | author=Andreae S, Buisson S, Triebel F |title=MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223). |journal=Blood |volume=102 |issue= 6 |pages= 2130-7 |year= 2003 |pmid= 12775570 |doi= 10.1182/blood-2003-01-0273 }}
* The first is [[IMP321]], a soluble LAG3 which activates [[dendritic cell]]s.<ref name=Avice1999>{{cite journal
*{{cite journal | author=Cai XF, Tao Z, Yan ZQ, ''et al.'' |title=Molecular cloning, characterisation and tissue-specific expression of human LAG3, a member of the novel Lag1 protein family. |journal=DNA Seq. |volume=14 |issue= 2 |pages= 79-86 |year= 2004 |pmid= 12825348 |doi= }}
  |author1=Avice M |author2=Sarfati M |author3=Triebel F |author4=Delespesse G |author5=Demeure CE. |title=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.
*{{cite journal | author=Gandhi MK, Lambley E, Duraiswamy J, ''et al.'' |title=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. |journal=Blood |volume=108 |issue= 7 |pages= 2280-9 |year= 2006 |pmid= 16757686 |doi= 10.1182/blood-2006-04-015164 }}
|journal=J. Immunol.
*{{cite journal  | author=Lundmark F, Harbo HF, Celius EG, ''et al.'' |title=Association analysis of the LAG3 and CD4 genes in multiple sclerosis in two independent populations. |journal=J. Neuroimmunol. |volume=180 |issue= 1-2 |pages= 193-8 |year= 2007 |pmid= 17020785 |doi= 10.1016/j.jneuroim.2006.08.009 }}
|volume=162
}}
|issue=5
|pages=:2748–53.
|date=March 1, 1999
|doi=  
|pmid=10072520
}}</ref>
* The second are antibodies to LAG3 which take the brakes off the anti-cancer immune response. An example is [[BMS-986016]], an anti-LAG3 monoclonal antibody that is currently in phase 1 clinical testing.<ref>{{ClinicalTrialsGov|NCT01968109|Safety Study of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors}}</ref> A number of additional LAG3 antibodies are in preclinical development.<ref>{{cite web|title=Tesaro's Immuno-Oncology Platform|url=http://www.tesarobio.com/immuno-oncology_portfolio|website=Tesaro web site}}</ref> 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 [[Regulatory T cell|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<ref>{{cite web|title=Technology Platforms |url=http://www.immutep.org/ProductDevelopment/TechnologyPlatform |publisher=Immutep |accessdate=1 July 2015 |deadurl=yes |archiveurl=https://web.archive.org/web/20150701100823/http://www.immutep.org/ProductDevelopment/TechnologyPlatform |archivedate= 1 July 2015 |df= }}</ref>
* The third are 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]]).<ref>[https://www.clinicaltrials.gov/ct2/show/NCT02195349 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]</ref>
 
== History ==
 
===1990 to 1999===
LAG3 was discovered in 1990 by [[Frédéric Triebel]] when he headed the cellular immunology group in the Department of Clinical Biology at the [[Institut Gustave Roussy]].<ref>{{cite journal | vauthors = Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T | title = LAG-3, a novel lymphocyte activation gene closely related to CD4 | journal = The Journal of Experimental Medicine | volume = 171 | issue = 5 | pages = 1393–405 | date = May 1990 | pmid = 1692078 | pmc = 2187904 | doi=10.1084/jem.171.5.1393}}</ref> An initial characterization of the LAG-3 protein was reported in 1992 showing that it was a ligand for MHC class II antigens<ref>{{cite journal | vauthors = Baixeras E, Huard B, Miossec C, Jitsukawa S, Martin M, Hercend T, Auffray C, Triebel F, Piatier-Tonneau D | title = Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens | journal = The Journal of Experimental Medicine | volume = 176 | issue = 2 | pages = 327–37 | date = Aug 1992 | pmid = 1380059 | doi =  10.1084/jem.176.2.327 | pmc=2119326}}</ref> while a 1995 paper showed that it bound MHC Class II better than CD4.<ref name="Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F. 2718–21"/> In 1996 [[INSERM]] scientists from [[Strasbourg]] showed, in [[Knockout mouse|knockout mice]] that were deficient in both CD4 and LAG-3, that the two proteins were not functionally equivalent.<ref>{{cite journal | vauthors = Miyazaki T, Dierich A, Benoist C, Mathis D | title = LAG-3 is not responsible for selecting T helper cells in CD4-deficient mice | journal = International Immunology | volume = 8 | issue = 5 | pages = 725–9 | date = May 1996 | pmid = 8671660 | doi =  10.1093/intimm/8.5.725}}</ref> The first characterization of the MHC Class II binding sites on LAG-3 were reported by Triebel's group in 1997.<ref>{{cite journal | vauthors = Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, Maigret B, Dréano M, Triebel F | title = Characterization of the major histocompatibility complex class II binding site on LAG-3 protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 11 | pages = 5744–9 | date = May 1997 | pmid = 9159144 | doi =  10.1073/pnas.94.11.5744 | pmc=20850}}</ref> The phenotype of LAG-3 [[Knockout mouse|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]]<ref>{{cite journal | vauthors = Miyazaki T, Dierich A, Benoist C, Mathis D | title = Independent modes of natural killing distinguished in mice lacking Lag3 | journal = Science | volume = 272 | issue = 5260 | pages = 405–8 | date = Apr 1996 | pmid = 8602528 | doi =  10.1126/science.272.5260.405}}</ref> 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.<ref>{{cite journal | vauthors = Huard B, Tournier M, Triebel F | title = LAG-3 does not define a specific mode of natural killing in human | journal = Immunology Letters | volume = 61 | issue = 2–3 | pages = 109–12 | date = Apr 1998 | pmid = 9657262 | doi = 10.1016/s0165-2478(97)00170-3}}</ref>
 
In May 1996 scientists at the [[University of Florence]] showed that CD4<sup>+</sup> T cells that were LAG-3<sup>+</sup> preferentially expressed [[Interferon gamma|IFN-γ]], and this was up-regulated by [[Interleukin 12|IL-12]]<ref>{{cite journal | vauthors = Annunziato F, Manetti R, Tomasévic I, Guidizi MG, Biagiotti R, Giannò V, Germano P, Mavilia C, Maggi E, Romagnani S | title = Expression and release of LAG-3-encoded protein by human CD4<sup>+</sup> T cells are associated with IFN-gamma production | journal = FASEB Journal | volume = 10 | issue = 7 | pages = 769–76 | date = May 1996 | pmid = 8635694 | doi =  }}</ref> 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.<ref>{{cite journal | vauthors = Annunziato F, Manetti R, Cosmi L, Galli G, Heusser CH, Romagnani S, Maggi E | title = Opposite role for interleukin-4 and interferon-gamma on CD30 and lymphocyte activation gene-3 (LAG-3) expression by activated naive T cells | journal = European Journal of Immunology | volume = 27 | issue = 9 | pages = 2239–44 | date = Sep 1997 | pmid = 9341765 | doi = 10.1002/eji.1830270918 }}</ref> 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.<ref>{{cite journal | vauthors = Scala E, Carbonari M, Del Porto P, Cibati M, Tedesco T, Mazzone AM, Paganelli R, Fiorilli M | title = Lymphocyte activation gene-3 (LAG-3) expression and IFN-gamma production are variably coregulated in different human T lymphocyte subpopulations | journal = Journal of Immunology | volume = 161 | issue = 1 | pages = 489–93 | date = Jul 1998 | pmid = 9647260 | doi =  }}</ref> The Triebel group in 1998 established that LAG-3 expression on activated human T cells is upregulated by [[Interleukin 2|IL-2]], [[Interleukin 7|IL-7]] and IL-12 and also showed that expression of LAG-3 may be controlled by some CD4 regulatory elements.<ref>{{cite journal | vauthors = Bruniquel D, Borie N, Hannier S, Triebel F | title = Regulation of expression of the human lymphocyte activation gene-3 (LAG-3) molecule, a ligand for MHC class II | journal = Immunogenetics | volume = 48 | issue = 2 | pages = 116–24 | date = Jul 1998 | pmid = 9634475 | doi =  10.1007/s002510050411}}</ref> 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.<ref>{{cite journal | vauthors = Hannier S, Tournier M, Bismuth G, Triebel F | title = CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling | journal = Journal of Immunology | volume = 161 | issue = 8 | pages = 4058–65 | date = Oct 1998 | pmid = 9780176 | doi =  }}</ref> This relationship was confirmed in 1999 with co-capping experiments and with conventional fluorescence microscopy.<ref>{{cite journal | vauthors = Hannier S, Triebel F | title = 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 | journal = International Immunology | volume = 11 | issue = 11 | pages = 1745–52 | date = Nov 1999 | pmid = 10545478 | doi =  10.1093/intimm/11.11.1745}}</ref> In 1999 Triebel showed that LAG-3 could be used as a cancer vaccine, through cancer cell lines transfected with LAG-3.<ref>{{cite journal | vauthors = Prigent P, El Mir S, Dréano M, Triebel F | title = Lymphocyte activation gene-3 induces tumor regression and antitumor immune responses | journal = European Journal of Immunology | volume = 29 | issue = 12 | pages = 3867–76 | date = Dec 1999 | pmid = 10601994 | doi = 10.1002/(SICI)1521-4141(199912)29:12<3867::AID-IMMU3867>3.0.CO;2-E }}</ref>
 
===2000 to 2009.===
In 2001 the Triebel group identified a LAG3-associated protein, called LAP, that seemed to participate in immune system down-regulation.<ref>{{cite journal | vauthors = Iouzalen N, Andreae S, Hannier S, Triebel F | title = 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 | journal = European Journal of Immunology | volume = 31 | issue = 10 | pages = 2885–91 | date = Oct 2001 | pmid = 11592063 | doi = 10.1002/1521-4141(2001010)31:10<2885::AID-IMMU2885>3.0.CO;2-2 }}</ref> Also in 2001 the Triebel group reported finding LAG3 expression on CD8<sup>+</sup> [[tumor-infiltrating lymphocytes]], with this LAG3 contributing to APC activation.<ref>{{cite journal | vauthors = Demeure CE, Wolfers J, Martin-Garcia N, Gaulard P, Triebel F | title = T Lymphocytes infiltrating various tumour types express the MHC class II ligand lymphocyte activation gene-3 (LAG-3): role of LAG-3/MHC class II interactions in cell-cell contacts | journal = European Journal of Cancer | volume = 37 | issue = 13 | pages = 1709–18 | date = Sep 2001 | pmid = 11527700 | doi =  10.1016/s0959-8049(01)00184-8}}</ref> 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, Tennessee|Memphis]].<ref>{{cite journal | vauthors = Workman CJ, Rice DS, Dugger KJ, Kurschner C, Vignali DA | title = Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3) | journal = European Journal of Immunology | volume = 32 | issue = 8 | pages = 2255–63 | date = Aug 2002 | pmid = 12209638 | doi = 10.1002/1521-4141(200208)32:8<2255::AID-IMMU2255>3.0.CO;2-A }}</ref> 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.<ref>{{cite journal | vauthors = Workman CJ, Dugger KJ, Vignali DA | title = Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3 | journal = Journal of Immunology | volume = 169 | issue = 10 | pages = 5392–5 | date = Nov 2002 | pmid = 12421911 | doi =  10.4049/jimmunol.169.10.5392}}</ref> In 2003 the Triebel group was able to identify the MHC class II signal transduction pathways in human dendritic cells induced by LAG3.<ref>{{cite journal | vauthors = Andreae S, Buisson S, Triebel F | title = MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223) | journal = Blood | volume = 102 | issue = 6 | pages = 2130–7 | date = Sep 2003 | pmid = 12775570 | doi = 10.1182/blood-2003-01-0273 }}</ref> while the St. Jude Children's Research Hospital team showed that the absence of LAG3 caused no defect in T cell function.<ref name="Workman CJ, Vignali DA. :970–9"/>
 
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.<ref name="Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA 5450–5"/> This was in spite of earlier ''in vitro'' work that seemed to suggest that LAG-3 was necessary for T cell expansion.<ref name="Workman CJ, Vignali DA. :970–9"/> Work at [[Johns Hopkins University]] published in October 2004 identified LAG3's key role in regulatory T cells.<ref name="Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA 503–13"/> 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.<ref>{{cite journal | vauthors = Li N, Workman CJ, Martin SM, Vignali DA | title = Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223) | journal = Journal of Immunology | volume = 173 | issue = 11 | pages = 6806–12 | date = Dec 2004 | pmid = 15557174 | doi =  10.4049/jimmunol.173.11.6806}}</ref>
 
In January 2005 scientists at the [[Gabriele 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.<ref>{{cite journal | vauthors = Di Carlo E, Cappello P, Sorrentino C, D'Antuono T, Pellicciotta A, Giovarelli M, Forni G, Musiani P, Triebel F | title = 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 | journal = The Journal of Pathology | volume = 205 | issue = 1 | pages = 82–91 | date = Jan 2005 | pmid = 15586367 | doi = 10.1002/path.1679 }}</ref> Scientists working with [[AstraZeneca]] reported in March 2005 that SNPs on LAG3 conferred susceptibility to [[multiple sclerosis]]<ref>{{cite journal | vauthors = Zhang Z, Duvefelt K, Svensson F, Masterman T, Jonasdottir G, Salter H, Emahazion T, Hellgren D, Falk G, Olsson T, Hillert J, Anvret M | title = Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis | journal = Genes and Immunity | volume = 6 | issue = 2 | pages = 145–52 | date = Mar 2005 | pmid = 15674389 | doi = 10.1038/sj.gene.6364171 }}</ref> although later work at the [[Karolinska Institute]] showed no significant association.<ref>{{cite journal | vauthors = Lundmark F, Harbo HF, Celius EG, Saarela J, Datta P, Oturai A, Lindgren CM, Masterman T, Salter H, Hillert J | title = Association analysis of the LAG3 and CD4 genes in multiple sclerosis in two independent populations | journal = Journal of Neuroimmunology | volume = 180 | issue = 1–2 | pages = 193–8 | date = Nov 2006 | pmid = 17020785 | doi = 10.1016/j.jneuroim.2006.08.009 }}</ref> 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.<ref>{{cite journal | vauthors = Maçon-Lemaître L, Triebel F | title = The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells | journal = Immunology | volume = 115 | issue = 2 | pages = 170–8 | date = Jun 2005 | pmid = 15885122 | doi = 10.1111/j.1365-2567.2005.02145.x | pmc=1782137}}</ref> 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<ref name="ReferenceA"/>
 
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.<ref>{{cite journal | vauthors = Ausiello CM, Palazzo R, Spensieri F, Urbani F, Massari M, Triebel F, Benagiano M, D'Elios MM, Del Prete G, Cassone A | title = Soluble CD30 and lymphocyte activation gene-3 (CD223), as potential serological markers of T helper-type cytokine response induced by acellular pertussis vaccine | journal = International Journal of Immunopathology and Pharmacology | volume = 19 | issue = 1 | pages = 97–104 | date = January 1, 2006 | pmid = 16569347 | doi =  }}</ref>
 
In April 2007 scientists working at [[Edward Jenner Institute for Vaccine Research]] in the UK demonstrated that LAG-3 participates in [[Regulatory T cell|Treg]]-induced upregulation of [[CCR7]] and [[CXCR4]] on dendritic cells, resulting in semi-mature dendritic cells with the ability to migrate into lymphoid organs.<ref>{{cite journal | vauthors = Bayry J, Triebel F, Kaveri SV, Tough DF | title = Human dendritic cells acquire a semimature phenotype and lymph node homing potential through interaction with CD4<sup>+</sup>CD25+ regulatory T cells | journal = Journal of Immunology | volume = 178 | issue = 7 | pages = 4184–93 | date = Apr 2007 | pmid = 17371975 | doi =  10.4049/jimmunol.178.7.4184}}</ref> Scientists at [[Sun Yat-sen University]] in China showed that LAG-3 played a role in [[immune privilege]] in the eye.<ref>{{cite journal | vauthors = Zhu X, Yang P, Zhou H, Li B, Huang X, Meng Q, Wang L, Kijlstra A | title = CD4+CD25+Tregs express an increased LAG-3 and CTLA-4 in anterior chamber-associated immune deviation | journal = Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht von Graefes Archiv für Klinische und Experimentelle Ophthalmologie | volume = 245 | issue = 10 | pages = 1549–57 | date = Oct 2007 | pmid = 17541623 | doi = 10.1007/s00417-007-0591-8 }}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems | journal = The Journal of Clinical Investigation | volume = 117 | issue = 11 | pages = 3383–92 | date = Nov 2007 | pmid = 17932562 | doi = 10.1172/JCI31184 | pmc=2000807}}</ref>
 
In 2009 the St. Jude Children's Research Hospital group reported that LAG3 appeared on plasmacytoid dendritic cells.<ref name="ReferenceB"/> Scientists at the [[University of Tokyo]] showed that LAG-3 was a marker of Tregs that secrete IL-10.<ref>{{cite journal | vauthors = Okamura T, Fujio K, Shibuya M, Sumitomo S, Shoda H, Sakaguchi S, Yamamoto K | title = CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 33 | pages = 13974–9 | date = Aug 2009 | pmid = 19666526 | doi = 10.1073/pnas.0906872106 | pmc=2729005}}</ref>
 
===2010 to 2015.===
In 2010 scientists at [[ETH Zurich|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.<ref>{{cite journal | vauthors = Richter K, Agnellini P, Oxenius A | title = On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection | journal = International Immunology | volume = 22 | issue = 1 | pages = 13–23 | date = Jan 2010 | pmid = 19880580 | doi = 10.1093/intimm/dxp107 }}</ref> Scientists the University Hospital [[Brno]] showed that LAG3 is a prognostic indicator of poor treatment outcomes in [[chronic lymphocytic leukemia]].<ref>{{cite journal | vauthors = Kotaskova J, Tichy B, Trbusek M, Francova HS, Kabathova J, Malcikova J, Doubek M, Brychtova Y, Mayer J, Pospisilova S | title = High expression of lymphocyte-activation gene 3 (LAG3) in chronic lymphocytic leukemia cells is associated with unmutated immunoglobulin variable heavy chain region (IGHV) gene and reduced treatment-free survival | journal = The Journal of Molecular Diagnostics | volume = 12 | issue = 3 | pages = 328–34 | date = May 2010 | pmid = 20228263 | doi = 10.2353/jmoldx.2010.090100 | pmc=2860469}}</ref> A team at the [[Roswell Park Cancer Institute]] showed that CD8+ [[Tumor-infiltrating lymphocyte]]s that were specific for NY-ESO-1 were negatively regulated by LAG-3 and PD-1 in ovarian cancer.<ref>{{cite journal | vauthors = 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 | title = Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 17 | pages = 7875–80 | date = Apr 2010 | pmid = 20385810 | doi = 10.1073/pnas.1003345107 | pmc=2867907}}</ref> 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.<ref>{{cite journal | vauthors = Woo SR, Li N, Bruno TC, Forbes K, Brown S, Workman C, Drake CG, Vignali DA | title = Differential subcellular localization of the regulatory T-cell protein LAG-3 and the coreceptor CD4 | journal = European Journal of Immunology | volume = 40 | issue = 6 | pages = 1768–77 | date = Jun 2010 | pmid = 20391435 | doi = 10.1002/eji.200939874 | pmc=2987677}}</ref> 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.<ref>{{cite journal | vauthors = Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, Parmiani G, Belli F, Rivoltini L, Castelli C | title = LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites | journal = Journal of Immunology | volume = 184 | issue = 11 | pages = 6545–51 | date = Jun 2010 | pmid = 20421648 | doi = 10.4049/jimmunol.0903879 }}</ref> Geneticists working at the [[National Cancer Institute]] reported that [[Single-nucleotide polymorphism|SNPs]] in the LAG3 gene were associated with higher risk of [[multiple myeloma]].<ref>{{cite journal | vauthors = 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 | title = Common single nucleotide polymorphisms in immunoregulatory genes and multiple myeloma risk among women in Connecticut | journal = American Journal of Hematology | volume = 85 | issue = 8 | pages = 560–3 | date = Aug 2010 | pmid = 20568250 | doi = 10.1002/ajh.21760 | pmc=2910184}}</ref>
 
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.<ref>{{cite journal | vauthors = Lucas CL, Workman CJ, Beyaz S, LoCascio S, Zhao G, Vignali DA, Sykes M | title = LAG-3, TGF-β, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L | journal = Blood | volume = 117 | issue = 20 | pages = 5532–40 | date = May 2011 | pmid = 21422469 | doi = 10.1182/blood-2010-11-318675 | pmc=3109721}}</ref> 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.<ref>{{cite journal | vauthors = Hemon P, Jean-Louis F, Ramgolam K, Brignone C, Viguier M, Bachelez H, Triebel F, Charron D, Aoudjit F, Al-Daccak R, Michel L | title = MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis | journal = Journal of Immunology | volume = 186 | issue = 9 | pages = 5173–83 | date = May 2011 | pmid = 21441454 | doi = 10.4049/jimmunol.1002050 }}</ref> The St. Jude Children's Research Hospital group showed that LAG3 can play a modulating role in autoimmune diabetes.<ref>{{cite journal | vauthors = Bettini M, Szymczak-Workman AL, Forbes K, Castellaw AH, Selby M, Pan X, Drake CG, Korman AJ, Vignali DA | title = Cutting edge: accelerated autoimmune diabetes in the absence of LAG-3 | journal = Journal of Immunology | volume = 187 | issue = 7 | pages = 3493–8 | date = Oct 2011 | pmid = 21873518 | doi = 10.4049/jimmunol.1100714 | pmc=3178660}}</ref> Microbiologists at the [[University of Iowa]] demonstrated that blockade of PD-L1 and LAG-3 was a valid therapeutic strategy for [[Plasmodium]] infection.<ref>{{cite journal | vauthors = Butler NS, Moebius J, Pewe LL, Traore B, Doumbo OK, Tygrett LT, Waldschmidt TJ, Crompton PD, Harty JT | title = Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection | journal = Nature Immunology | volume = 13 | issue = 2 | pages = 188–95 | date = Feb 2012 | pmid = 22157630 | doi = 10.1038/ni.2180 | pmc=3262959}}</ref>
 
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.<ref>{{cite journal | vauthors = 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 | title = Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape | journal = Cancer Research | volume = 72 | issue = 4 | pages = 917–27 | date = Feb 2012 | pmid = 22186141 | doi = 10.1158/0008-5472.CAN-11-1620 | pmc=3288154}}</ref> 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.<ref>{{cite journal | vauthors = Cho H, Chung YH | title = Construction, and in vitro and in vivo analyses of tetravalent immunoadhesins | journal = Journal of Microbiology and Biotechnology | volume = 22 | issue = 8 | pages = 1066–76 | date = Aug 2012 | pmid = 22713982 | doi = 10.4014/jmb.1201.01026}}</ref> In 2013 scientists at the San Raffaele Scientific Institute in Milan showed that LAG3 was a marker of type 1 Tregs.<ref>{{cite journal | vauthors = 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 | title = Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells | journal = Nature Medicine | volume = 19 | issue = 6 | pages = 739–46 | date = Jun 2013 | pmid = 23624599 | doi = 10.1038/nm.3179 }}</ref>
 
In 2014 scientists at [[Stanford University]] showed that LAG engagement could diminish alloreactive T cell responses after [[bone marrow transplantation]].<ref>{{cite journal | vauthors = Sega EI, Leveson-Gower DB, Florek M, Schneidawind D, Luong RH, Negrin RS | title = Role of lymphocyte activation gene-3 (Lag-3) in conventional and regulatory T cell function in allogeneic transplantation | journal = PLOS ONE | volume = 9 | issue = 1 | pages = e86551 | date = January 27, 2014 | pmid = 24475140 | doi = 10.1371/journal.pone.0086551 | pmc=3903521}}</ref> 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.<ref>{{cite journal | vauthors = Peña J, Jones NG, Bousheri S, Bangsberg DR, Cao H | title = Lymphocyte activation gene-3 expression defines a discrete subset of HIV-specific CD8+ T cells that is associated with lower viral load | journal = AIDS Research and Human Retroviruses | volume = 30 | issue = 6 | pages = 535–41 | date = Jun 2014 | pmid = 24180338 | doi = 10.1089/AID.2012.0195 | pmc=4046223}}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3 | journal = The Journal of Investigative Dermatology | volume = 134 | issue = 7 | pages = 1893–902 | date = Jul 2014 | pmid = 24441096 | doi = 10.1038/jid.2014.29 }}</ref> 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.<ref>{{cite journal | vauthors = Bae J, Lee SJ, Park CG, Lee YS, Chun T | title = Trafficking of LAG-3 to the surface on activated T cells via its cytoplasmic domain and protein kinase C signaling | journal = Journal of Immunology | volume = 193 | issue = 6 | pages = 3101–12 | date = Sep 2014 | pmid = 25108024 | doi = 10.4049/jimmunol.1401025 }}</ref>
 
In 2015 scientists at the [[University of Tokyo]] showed how LAG3 on Tregs work with [[TGF beta 3]] to suppress antibody production.<ref>{{cite journal | vauthors = Okamura T, Sumitomo S, Morita K, Iwasaki Y, Inoue M, Nakachi S, Komai T, Shoda H, Miyazaki J, Fujio K, Yamamoto K | title = TGF-β3-expressing CD4+CD25(-)LAG3+ regulatory T cells control humoral immune responses | journal = Nature Communications | volume = 6 | issue = 6329 | pages = 6329 | date = February 19, 2015 | pmid = 25695838 | doi = 10.1038/ncomms7329 | pmc=4346620}}</ref> At [[Tulane University]] bacteriologists working at the Tulane National Primate Research Center showed in [[rhesus macaque]]s that ''[[Mycobacterium tuberculosis]]'' could work through LAG3 to modulate an anti-bacterial immune response.<ref>{{cite journal | vauthors = Phillips BL, Mehra S, Ahsan MH, Selman M, Khader SA, Kaushal D | title = LAG3 expression in active Mycobacterium tuberculosis infections | journal = The American Journal of Pathology | volume = 185 | issue = 3 | pages = 820–33 | date = Mar 2015 | pmid = 25549835 | doi = 10.1016/j.ajpath.2014.11.003 | pmc=4348466}}</ref> 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.<ref>{{cite journal | vauthors = Chu KH, Chiang BL | title = Characterization and functional studies of forkhead box protein 3(-) lymphocyte activation gene 3(+) CD4(+) regulatory T cells induced by mucosal B cells | journal = Clinical and Experimental Immunology | volume = 180 | issue = 2 | pages = 316–28 | date = May 2015 | pmid = 25581421 | doi = 10.1111/cei.12583 | pmc=4408166}}</ref>
 
== References ==
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Triebel F | title = LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination | journal = Trends in Immunology | volume = 24 | issue = 12 | pages = 619–22 | date = Dec 2003 | pmid = 14644131 | doi = 10.1016/j.it.2003.10.001 }}
* {{cite journal | vauthors = Baixeras E, Huard B, Miossec C, Jitsukawa S, Martin M, Hercend T, Auffray C, Triebel F, Piatier-Tonneau D | title = Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens | journal = The Journal of Experimental Medicine | volume = 176 | issue = 2 | pages = 327–37 | date = Aug 1992 | pmid = 1380059 | pmc = 2119326 | doi = 10.1084/jem.176.2.327 }}
* {{cite journal | vauthors = Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T | title = LAG-3, a novel lymphocyte activation gene closely related to CD4 | journal = The Journal of Experimental Medicine | volume = 171 | issue = 5 | pages = 1393–405 | date = May 1990 | pmid = 1692078 | pmc = 2187904 | doi = 10.1084/jem.171.5.1393 }}
* {{cite journal | vauthors = Blum MD, Wong GT, Higgins KM, Sunshine MJ, Lacy E | title = Reconstitution of the subclass-specific expression of CD4 in thymocytes and peripheral T cells of transgenic mice: identification of a human CD4 enhancer | journal = The Journal of Experimental Medicine | volume = 177 | issue = 5 | pages = 1343–58 | date = May 1993 | pmid = 8097522 | pmc = 2191022 | doi = 10.1084/jem.177.5.1343 }}
* {{cite journal | vauthors = Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, Maigret B, Dréano M, Triebel F | title = Characterization of the major histocompatibility complex class II binding site on LAG-3 protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 11 | pages = 5744–9 | date = May 1997 | pmid = 9159144 | pmc = 20850 | doi = 10.1073/pnas.94.11.5744 }}
* {{cite journal | vauthors = Bruniquel D, Borie N, Triebel F | title = Genomic organization of the human LAG-3/CD4 locus | journal = Immunogenetics | volume = 47 | issue = 1 | pages = 96–8 | year = 1998 | pmid = 9382927 | doi = 10.1007/s002510050332 }}
* {{cite journal | vauthors = Bruniquel D, Borie N, Hannier S, Triebel F | title = Regulation of expression of the human lymphocyte activation gene-3 (LAG-3) molecule, a ligand for MHC class II | journal = Immunogenetics | volume = 48 | issue = 2 | pages = 116–24 | date = Jul 1998 | pmid = 9634475 | doi = 10.1007/s002510050411 }}
* {{cite journal | vauthors = Hannier S, Tournier M, Bismuth G, Triebel F | title = CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling | journal = Journal of Immunology | volume = 161 | issue = 8 | pages = 4058–65 | date = Oct 1998 | pmid = 9780176 | doi =  }}
* {{cite journal | vauthors = Hannier S, Triebel F | title = 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 | journal = International Immunology | volume = 11 | issue = 11 | pages = 1745–52 | date = Nov 1999 | pmid = 10545478 | doi = 10.1093/intimm/11.11.1745 }}
* {{cite journal | vauthors = Iouzalen N, Andreae S, Hannier S, Triebel F | title = 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 | journal = European Journal of Immunology | volume = 31 | issue = 10 | pages = 2885–91 | date = Oct 2001 | pmid = 11592063 | doi = 10.1002/1521-4141(2001010)31:10<2885::AID-IMMU2885>3.0.CO;2-2 }}
* {{cite journal | vauthors = Andreae S, Piras F, Burdin N, Triebel F | title = Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223) | journal = Journal of Immunology | volume = 168 | issue = 8 | pages = 3874–80 | date = Apr 2002 | pmid = 11937541 | doi = 10.4049/jimmunol.168.8.3874 }}
* {{cite journal | vauthors = Andreae S, Buisson S, Triebel F | title = MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223) | journal = Blood | volume = 102 | issue = 6 | pages = 2130–7 | date = Sep 2003 | pmid = 12775570 | doi = 10.1182/blood-2003-01-0273 }}
* {{cite journal | vauthors = Cai XF, Tao Z, Yan ZQ, Yang SL, Gong Y | title = Molecular cloning, characterisation and tissue-specific expression of human LAG3, a member of the novel Lag1 protein family | journal = DNA Sequence | volume = 14 | issue = 2 | pages = 79–86 | date = Apr 2003 | pmid = 12825348 | doi = 10.1080/1042517021000041831 }}
* {{cite journal | vauthors = Gandhi MK, Lambley E, Duraiswamy J, Dua U, Smith C, Elliott S, Gill D, Marlton P, Seymour J, Khanna R | title = Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8<sup>+</sup> T-cell function in Hodgkin lymphoma patients | journal = Blood | volume = 108 | issue = 7 | pages = 2280–9 | date = Oct 2006 | pmid = 16757686 | doi = 10.1182/blood-2006-04-015164 }}
* {{cite journal | vauthors = Lundmark F, Harbo HF, Celius EG, Saarela J, Datta P, Oturai A, Lindgren CM, Masterman T, Salter H, Hillert J | title = Association analysis of the LAG3 and CD4 genes in multiple sclerosis in two independent populations | journal = Journal of Neuroimmunology | volume = 180 | issue = 1–2 | pages = 193–8 | date = Nov 2006 | pmid = 17020785 | doi = 10.1016/j.jneuroim.2006.08.009 }}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|LAG3+protein,+human}}
* {{MeshName|LAG3+protein,+human}}


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{{NLM content}}
{{Clusters of differentiation}}
{{Clusters of differentiation}}
[[Category:Clusters of differentiation]]
[[Category:Clusters of differentiation]]
{{WikiDoc Sources}}

Revision as of 03:32, 11 November 2017

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Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene.[1] LAG3, which was discovered in 1990[2] and was designated CD223 (cluster of differentiation 223) after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000,[3] 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.

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.[1] 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[4]

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. 70% homology with murine LAG3.[2] The homology of pig LAG3 is 78%.[5]

Tissue distribution

LAG-3 is expressed on activated T cells,[6] natural killer cells,[2] B cells[7] and plasmacytoid dendritic cells.[8]

Function

LAG3's main ligand is MHC class II, to which it binds with higher affinity than CD4.[9] The protein negatively regulates cellular proliferation, activation, and homeostasis of T cells, in a similar fashion to CTLA-4 and PD-1[10][11] and has been reported to play a role in Treg suppressive function.[12]

LAG3 also helps maintain CD8+ T cells in a tolerogenic state[4] and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection.[13]

LAG3 is known to be involved in the maturation and activation of dendritic cells.[14]

Use as a pharmaceutical and as a drug target

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

  • The first is IMP321, a soluble LAG3 which activates dendritic cells.[15]
  • The second are antibodies to LAG3 which take the brakes off the anti-cancer immune response. An example is BMS-986016, an anti-LAG3 monoclonal antibody that is currently in phase 1 clinical testing.[16] A number of additional LAG3 antibodies are in preclinical development.[17] 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[18]
  • The third are 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).[19]

History

1990 to 1999

LAG3 was discovered in 1990 by Frédéric Triebel when he headed the cellular immunology group in the Department of Clinical Biology at the Institut Gustave Roussy.[20] An initial characterization of the LAG-3 protein was reported in 1992 showing that it was a ligand for MHC class II antigens[21] while a 1995 paper showed that it bound MHC Class II better than CD4.[9] 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.[22] The first characterization of the MHC Class II binding sites on LAG-3 were reported by Triebel's group in 1997.[23] 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[24] 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.[25]

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[26] 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.[27] 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.[28] 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.[29] 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.[30] This relationship was confirmed in 1999 with co-capping experiments and with conventional fluorescence microscopy.[31] In 1999 Triebel showed that LAG-3 could be used as a cancer vaccine, through cancer cell lines transfected with LAG-3.[32]

2000 to 2009.

In 2001 the Triebel group identified a LAG3-associated protein, called LAP, that seemed to participate in immune system down-regulation.[33] Also in 2001 the Triebel group reported finding LAG3 expression on CD8+ tumor-infiltrating lymphocytes, with this LAG3 contributing to APC activation.[34] 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.[35] 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.[36] In 2003 the Triebel group was able to identify the MHC class II signal transduction pathways in human dendritic cells induced by LAG3.[37] while the St. Jude Children's Research Hospital team showed that the absence of LAG3 caused no defect in T cell function.[10]

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.[11] This was in spite of earlier in vitro work that seemed to suggest that LAG-3 was necessary for T cell expansion.[10] Work at Johns Hopkins University published in October 2004 identified LAG3's key role in regulatory T cells.[12] 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.[38]

In January 2005 scientists at the Gabriele 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.[39] Scientists working with AstraZeneca reported in March 2005 that SNPs on LAG3 conferred susceptibility to multiple sclerosis[40] although later work at the Karolinska Institute showed no significant association.[41] 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.[42] 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[7]

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.[43]

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.[44] Scientists at Sun Yat-sen University in China showed that LAG-3 played a role in immune privilege in the eye.[45] 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.[46]

In 2009 the St. Jude Children's Research Hospital group reported that LAG3 appeared on plasmacytoid dendritic cells.[8] Scientists at the University of Tokyo showed that LAG-3 was a marker of Tregs that secrete IL-10.[47]

2010 to 2015.

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.[48] Scientists the University Hospital Brno showed that LAG3 is a prognostic indicator of poor treatment outcomes in chronic lymphocytic leukemia.[49] A team at the Roswell Park Cancer Institute 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.[50] 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.[51] 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.[52] Geneticists working at the National Cancer Institute reported that SNPs in the LAG3 gene were associated with higher risk of multiple myeloma.[53]

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.[54] 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.[55] The St. Jude Children's Research Hospital group showed that LAG3 can play a modulating role in autoimmune diabetes.[56] Microbiologists at the University of Iowa demonstrated that blockade of PD-L1 and LAG-3 was a valid therapeutic strategy for Plasmodium infection.[57]

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.[58] 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.[59] In 2013 scientists at the San Raffaele Scientific Institute in Milan showed that LAG3 was a marker of type 1 Tregs.[60]

In 2014 scientists at Stanford University showed that LAG engagement could diminish alloreactive T cell responses after bone marrow transplantation.[61] 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.[62] 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.[63] 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.[64]

In 2015 scientists at the University of Tokyo showed how LAG3 on Tregs work with TGF beta 3 to suppress antibody production.[65] 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.[66] 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.[67]

References

  1. ↑ 1.0 1.1 "Entrez Gene: LAG3 lymphocyte-activation gene 3".
  2. ↑ 2.0 2.1 2.2 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.
  3. ↑ Mason D, André P, Bensussan A, Buckley C, Civin C, Clark E, de Haas M, Goyert S, Hadam M, Hart D, Horejsí 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. PMID 11698486.
  4. ↑ 4.0 4.1 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.
  5. ↑ 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.
  6. ↑ Huard B, Gaulard P, Faure F, Hercend T, Triebel F (January 1, 1994). "Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand". Immunogenetics. 39 (3): 213–7. doi:10.1007/bf00241263. PMID 7506235.
  7. ↑ 7.0 7.1 Kisielow M, Kisielow J, Capoferri-Sollami G, Karjalainen K (Jul 2005). "Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells". European Journal of Immunology. 35 (7): 2081–8. doi:10.1002/eji.200526090. PMID 15971272.
  8. ↑ 8.0 8.1 Workman CJ, Wang Y, El Kasmi KC, Pardoll DM, Murray PJ, Drake CG, Vignali DA (Feb 2009). "LAG-3 regulates plasmacytoid dendritic cell homeostasis". Journal of Immunology. 182 (4): 1885–91. doi:10.4049/jimmunol.0800185. PMC 2675170. PMID 19201841.
  9. ↑ 9.0 9.1 Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F (Sep 1995). "CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins". European Journal of Immunology. 25 (9): 2718–21. doi:10.1002/eji.1830250949. PMID 7589152.
  10. ↑ 10.0 10.1 10.2 Workman CJ, Vignali DA (Apr 2003). "The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells". European Journal of Immunology. 33 (4): 970–9. doi:10.1002/eji.200323382. PMID 12672063.
  11. ↑ 11.0 11.1 Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA (May 2004). "Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo". Journal of Immunology. 172 (9): 5450–5. doi:10.4049/jimmunol.172.9.5450. PMID 15100286.
  12. ↑ 12.0 12.1 Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA (Oct 2004). "Role of LAG-3 in regulatory T cells". Immunity. 21 (4): 503–13. doi:10.1016/j.immuni.2004.08.010. PMID 15485628.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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. PMID 10072520.
  16. ↑ Clinical trial number NCT01968109 for "Safety Study of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors" at ClinicalTrials.gov
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