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of plasma membrane integral component of membrane plasma membrane biological process negative 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 ii sources amigo quickgo orthologs databases ncbi entry oma entry species human mouse 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 mb chr 6 124 88 124 89 mb pubmed search 3 4 wikidata view edit human view edit mouse 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 biological effects on t cell function but overall has an immune inhibitory effect it is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders in soluble form it is also being developed as a cancer drug in its own right 8 conservation of their respective cytoplasmic tail motifs cxc h in the case of cd4 and an itim like motif in the case of lag 3 supports that competition between cd4 and lag 3 for binding of kinase lck is a conserved core part of the jawed vertebrate immune system lag 3 is closely related to cd4 9 with which it shares the ability to bind mhc class ii molecules 10 although there has been conflicting information on which motifs in the lag 3 cytoplasmic tail are important for function 11 12 13 evolutionary conservation patterns 14 15 combined with functional studies 12 13 imply that the evolutionarily conserved core function of lag 3 is an inhibitory competition through an immunoreceptor tyrosine based inhibitory motif itim like motif with the activating receptors cd4 or cd8 for binding the kinase lck 14 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 16 and this gene organization can already be found in sharks 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 17 tissue distribution edit lag 3 is expressed on activated t cells 18 natural killer cells 6 b cells 19 and plasmacytoid dendritic cells 20 function edit lag3 s main ligand is mhc class ii to which it binds with higher affinity than cd4 10 the protein negatively regulates cellular proliferation activation 21 and homeostasis of t cells in a similar fashion to ctla 4 and pd 1 22 23 and has been reported to play a role in treg suppressive function 24 fibrinogen like protein1 fgl1 a liver secreted protein is another major lag3 functional ligand independent of mhc ii 25 lag3 also helps maintain cd8 t cells in a tolerogenic state 16 and working with pd 1 helps maintain cd8 exhaustion during chronic viral infection 26 lag3 is known to be involved in the maturation and activation of dendritic cells 27 lag3 has also been implicated in the transmission pathologic α synuclein in parkinson s disease 28 29 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 30 a soluble lag3 which activates dendritic cells 31 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 32 a number of additional lag3 antibodies are in preclinical development 33 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 34 combination therapies are also ongoing involving lag 3 antibodies and ctla 4 or pd 1 antibodies 8 32 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 35 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 9 an initial characterization of the lag 3 protein was reported in 1992 showing that it was a ligand for mhc class ii antigens 36 while a 1995 paper showed that it bound mhc class ii better than cd4 10 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 37 the first characterization of the mhc class ii binding sites on lag 3 were reported by triebel s group in 1997 38 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 39 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 40 in may 1996 cd4 t cells that were lag 3 were shown to preferentially express ifn γ which was up regulated by il 12 41 in 1997 it was demonstrated that ifn γ production drives lag 3 expression during the lineage commitment of human naive t cells 42 in 1998 further research showed that ifn γ is not required for the expression but rather for the up regulation of lag 3 43 lag 3 expression on activated human t cells is upregulated by il 2 il 7 and il 12 and its expression may be controlled by cd4 regulatory elements 44 it was also found that lag 3 down modulates t cell proliferation and activation when lag 3 mhc class ii co caps with the cd3 tcr complex 45 this was confirmed in 1999 with co capping experiments and fluorescence microscopy 46 in 1999 it was demonstrated that lag 3 could be used as a cancer vaccine through cancer cell lines transfected with lag 3 47 2000 to 2009 edit in 2001 a lag3 associated protein called lap was identified which appeared to participate in immune system down regulation 48 also in 2001 lag3 expression was found on cd8 tumor infiltrating lymphocytes with this lag3 contributing to apc activation 49 in august 2002 the first phenotypic analysis of the murine lag 3 was reported 50 molecular analysis in november 2002 demonstrated that the inhibitory function of lag 3 is performed via the protein s cytoplasmic domain 11 in 2003 mhc class ii signal transduction pathways in human dendritic cells induced by lag3 were identified 51 it was also shown that the absence of lag3 caused no defect in t cell function 22 in may 2004 it was shown through lag3 knockout mice that lag 3 negatively regulates t cell expansion and controls the size of the memory t cell pool 23 this was in contrast to earlier in vitro work suggesting that lag 3 was necessary for t cell expansion 22 research published in october 2004 identified lag3 s key role in regulatory t cells 24 in december 2004 it was reported that lag 3 is cleaved within the d4 transmembrane domain into two fragments that remain membrane associated a 54 kda fragment containing all the extracellular domains which oligomerizes with full length lag 3 70 kda on the cell surface via the d1 domain and a 16 kda peptide containing the transmembrane and cytoplasmic domains which is subsequently released as soluble lag 3 52 in january 2005 it was shown that lag 3 expression by tumor cells would recruit apcs into the tumor leading to a th1 immune response 53 in march 2005 it was reported that snps on lag3 conferred susceptibility to multiple sclerosis 54 however later work found no significant association 55 in june 2005 it was demonstrated that antibodies to lag 3 result in t cell expansion due to increased rounds of cell division that lag 3 signaling would normally block 56 in july 2005 it was established that lag3 expression on b cells is induced by t cells 19 in 2006 it was demonstrated that lag 3 could be used as a biomarker to assess the induction of th type responses in recipients of acellular pertussis vaccines 57 in april 2007 lag 3 was shown to participate in treg induced upregulation of ccr7 and cxcr4 on dendritic cells leading to the development of semi mature dendritic cells with the ability to migrate into lymphoid organs 58 lag 3 was also found to play a role in immune privilege in the eye 59 later in 2007 it was shown that lag 3 maintained tolerance to self and tumor antigens through both cd4 and cd8 cells independently of its role on treg cells 60 in 2009 lag 3 was reported to appear on plasmacytoid dendritic cells 20 it was also shown to be a marker of tregs that secrete il 10 61 2010 to 2015 edit in 2010 it was shown that lag3 is an exhaustion marker for cd8 t cells specific for lymphocytic choriomeningitis virus but alone did not significantly contribute to t cell exhaustion 62 cd8 tumor infiltrating lymphocytes specific for ny eso 1 were found to be negatively regulated by lag 3 and pd 1 in ovarian cancer 63 it was reported that most lag3 is 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 64 lag3 was also shown to define a potent regulatory t cell subset that is more frequently observed in cancer patients and expanded at tumor sites 65 additionally snps in the lag3 gene were associated with a higher risk of multiple myeloma 66 in 2011 it was reported that when antibodies to cd40l induced tolerance in allogeneic bone marrow transplantation lag3 played a role in the mechanism of action in cd8 cells 67 it was also shown that the binding of mhc class ii molecules on melanoma cells to lag3 increased resistance to apoptosis suggesting that antibodies to lag3 could be relevant in melanoma therapy 68 further research demonstrated that lag3 plays a modulating role in autoimmune diabetes 69 additionally blocking pd l1 and lag 3 was identified as a potential therapeutic strategy for plasmodium infection 70 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 71 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 72 in 2013 scientists at the san raffaele scientific institute in milan showed that lag3 was a marker of type 1 tregs 73 in 2014 it was shown that lag engagement could reduce alloreactive t cell responses following bone marrow transplantation 74 a subset of hiv specific lag3 cd8 t cells was identified which negatively correlated with plasma viral load 75 lag3 expression on plasmacytoid dendritic cells was found to contribute to creating an immune suppressive environment in melanoma 76 it was also demonstrated that lag 3 translocates to the cell surface in activated t cells via its cytoplasmic domain through protein kinase c signaling 77 in 2015 it was demonstrated that lag3 on tregs works with tgf beta 3 to suppress antibody production 78 additionally research in rhesus macaques showed that mycobacterium tuberculosis modulates the anti bacterial immune response through lag3 79 furthermore it was shown that lag3 plays a role in the immunosuppressive capacity of tregs stimulated by peyer s patch b cells 80 references edit 1 2 3 grch38 ensembl release 89 ensg00000089692 ensembl may 2017 1 2 3 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 1 2 entrez gene lag3 lymphocyte activation gene 3 1 2 3 triebel f jitsukawa s baixeras e roman roman s genevee c viegas pequignot e et al 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 andré p bensussan a buckley c civin c clark e et al nov 2001 cd antigens 2001 journal of leukocyte biology 70 5 685 90 doi 10 1189 jlb 70 5 685 pmid 11698486 s2cid 33478518 1 2 3 syn nl teng mw mok ts soo ra 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 1 2 triebel f jitsukawa s baixeras e roman roman s genevee c viegas pequignot e et al 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 1 2 3 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 s2cid 25894632 1 2 workman cj dugger kj vignali da nov 2002 cutting edge molecular analysis of the negative regulatory function of lymphocyte activation gene 3 journal of immunology 169 10 5392 5 doi 10 4049 jimmunol 169 10 5392 pmid 12421911 1 2 maeda tk sugiura d okazaki im maruhashi t okazaki t april 2019 atypical motifs in the cytoplasmic region of the inhibitory immune co receptor lag 3 inhibit t cell activation the journal of biological chemistry 294 15 6017 6026 doi 10 1074 jbc ra119 007455 pmc 6463702 pmid 30760527 1 2 guy c mitrea dm chou pc temirov j vignali km liu x et al may 2022 lag3 associates with tcr cd3 complexes and suppresses signaling by driving co receptor lck dissociation nature immunology 23 5 757 767 doi 10 1038 s41590 022 01176 4 pmc 9106921 pmid 35437325 1 2 takizawa f hashimoto k miyazawa r ohta y veríssimo a flajnik mf et al 2023 12 21 cd4 and lag 3 from sharks to humans related molecules with motifs for opposing functions frontiers in immunology 14 1267743 doi 10 3389 fimmu 2023 1267743 pmc 10768021 pmid 38187381 ohashi k takizawa f tokuma...