Lymphocyte-activation gene 3

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.

LAG3
Identifiers
Aliases	LAG3, CD223, lymphocyte activating 3
External IDs	OMIM: 153337; MGI: 106588; HomoloGene: 1719; GeneCards: LAG3; OMA:LAG3 - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12p13.31 Start 6,772,512 bp[1] End 6,778,455 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6|6 F2 Start 124,881,324 bp[2] End 124,888,668 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte right ovary left ovary gonad spleen testicle right lobe of liver body of uterus left uterine tube lymph node Top expressed in embryo embryo thymus zygote lip superior frontal gyrus epiblast granulocyte primary visual cortex ventricular zone More reference expression data BioGPS More reference expression data
Gene ontology Molecular function antigen binding transmembrane signaling receptor activity MHC class II protein binding Cellular component membrane external side 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 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

LAG-3 is closely related to CD4,^[9] with which it shares the ability to bind MHC class II molecules.^[10] Although there has been conflicting information on which motifs in the LAG-3 cytoplasmic tail are important for function,^[11][12][13] evolutionary conversation patterns^[14][15] combined with functional studies^[12][13] imply that the evolutionarily conserved core function of LAG-3 is 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

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

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

LAG-3 is expressed on activated T cells,^[18] natural killer cells,^[6] B cells^[19] and plasmacytoid dendritic cells.^[20]

Function

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

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

1990 to 1999

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.

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.

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

1. GRCh38: Ensembl release 89: ENSG00000089692 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000030124 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: LAG3 lymphocyte-activation gene 3".
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. Ohashi K, Takizawa F, Tokumaru N, Nakayasu C, Toda H, Fischer U, et al. (August 2010). "A molecule in teleost fish, related with human MHC-encoded G6F, has a cytoplasmic tail with ITAM and marks the surface of thrombocytes and in some fishes also of erythrocytes". Immunogenetics. 62 (8): 543–559. doi:10.1007/s00251-010-0460-1. PMID 20614118. S2CID 12282281.
16. Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, et al. (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.
17. Kim SS, Kim SH, Kang HS, Chung HY, Choi I, Cheon YP, et al. (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.
18. 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. S2CID 35247091.
19. 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. S2CID 12332458.
20. Workman CJ, Wang Y, El Kasmi KC, Pardoll DM, Murray PJ, Drake CG, et al. (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.
21. Huard B, Tournier M, Hercend T, Triebel F, Faure F (December 1994). "Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes". European Journal of Immunology. 24 (12): 3216–21. doi:10.1002/eji.1830241246. PMID 7805750.
22. 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. S2CID 46053425.
23. 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.
24. Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. (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.
25. Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, et al. (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.
26. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. (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.
27. 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.
28. Mao X, Gu H, Kim D, Kimura Y, Wang N, Xu E, et al. (May 2024). "Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein". Nature Communications. 15 (1): 4663. doi:10.1038/s41467-024-49016-3. PMC 11143359. PMID 38821932.
29. "New Study Suggests Cancer Drug Could Be Used to Target Protein Connection That Spurs Parkinson's Disease". Johns Hopkins Medicine. 17 June 2024.
30. "Oncology Pipeline at Immutep | Immunotherapy Treatment". www.immutep.com. Retrieved 2019-12-09.
31. Avice MN, Sarfati M, Triebel F, Delespesse G, Demeure CE (March 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". Journal of Immunology. 162 (5): 2748–2753. doi:10.4049/jimmunol.162.5.2748. PMID 10072520. S2CID 24564488.
32. 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
33. "Tesaro's Immuno-Oncology Platform". Tesaro web site.
34. "Technology Platforms". Immutep LAG-3. Archived from the original on 1 July 2015. Retrieved 1 July 2015.
35. 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
36. Baixeras E, Huard B, Miossec C, Jitsukawa S, Martin M, Hercend T, et al. (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.
37. 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.
38. Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, et al. (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.
39. 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.
40. 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.
41. Annunziato F, Manetti R, Tomasévic I, Guidizi MG, Biagiotti R, Giannò V, et al. (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.
42. Annunziato F, Manetti R, Cosmi L, Galli G, Heusser CH, Romagnani S, et al. (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.
43. Scala E, Carbonari M, Del Porto P, Cibati M, Tedesco T, Mazzone AM, et al. (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.
44. 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.
45. 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.
46. 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.
47. Prigent P, El Mir S, Dréano 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<3867::AID-IMMU3867>3.0.CO;2-E. PMID 10601994.
48. 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.
49. 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 class II interactions in cell-cell contacts". European Journal of Cancer. 37 (13): 1709–18. doi:10.1016/s0959-8049(01)00184-8. PMID 11527700.
50. Workman CJ, Rice DS, Dugger KJ, Kurschner C, Vignali DA (Aug 2002). "Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3)". European Journal of Immunology. 32 (8): 2255–63. doi:10.1002/1521-4141(200208)32:8<2255::AID-IMMU2255>3.0.CO;2-A. PMID 12209638.
51. 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.
52. Li N, Workman CJ, Martin SM, Vignali DA (Dec 2004). "Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223)". Journal of Immunology. 173 (11): 6806–12. doi:10.4049/jimmunol.173.11.6806. PMID 15557174.
53. Di Carlo E, Cappello P, Sorrentino C, D'Antuono T, Pellicciotta A, Giovarelli M, et al. (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.
54. Zhang Z, Duvefelt K, Svensson F, Masterman T, Jonasdottir G, Salter H, et al. (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.
55. Lundmark F, Harbo HF, Celius EG, Saarela J, Datta P, Oturai A, et al. (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.
56. Maçon-Lemaître 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.
57. Ausiello CM, Palazzo R, Spensieri F, Urbani F, Massari M, Triebel F, et al. (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.
58. 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.
59. Zhu X, Yang P, Zhou H, Li B, Huang X, Meng Q, et al. (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 für Klinische und Experimentelle Ophthalmologie. 245 (10): 1549–57. doi:10.1007/s00417-007-0591-8. PMID 17541623. S2CID 23556661.
60. Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, et al. (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.
61. Okamura T, Fujio K, Shibuya M, Sumitomo S, Shoda H, Sakaguchi S, et al. (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.
62. 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. hdl:20.500.11850/15681. PMID 19880580.
63. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. (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.
64. Woo SR, Li N, Bruno TC, Forbes K, Brown S, Workman C, et al. (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.
65. Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, et al. (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.
66. Lee KM, Baris D, Zhang Y, Hosgood HD, Menashe I, Yeager M, et al. (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.
67. Lucas CL, Workman CJ, Beyaz S, LoCascio S, Zhao G, Vignali DA, et al. (May 2011). "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". Blood. 117 (20): 5532–40. doi:10.1182/blood-2010-11-318675. PMC 3109721. PMID 21422469.
68. Hemon P, Jean-Louis F, Ramgolam K, Brignone C, Viguier M, Bachelez H, et al. (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.
69. Bettini M, Szymczak-Workman AL, Forbes K, Castellaw AH, Selby M, Pan X, et al. (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.
70. Butler NS, Moebius J, Pewe LL, Traore B, Doumbo OK, Tygrett LT, et al. (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.
71. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. (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.
72. 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.
73. Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, et al. (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.
74. 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.
75. Peña 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.
76. Camisaschi C, De Filippo A, Beretta V, Vergani B, Villa A, Vergani E, et al. (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.
77. 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.
78. Okamura T, Sumitomo S, Morita K, Iwasaki Y, Inoue M, Nakachi S, et al. (February 19, 2015). "TGF-β3-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.
79. 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.
80. 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

• 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, et al. (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, 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.
• 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, et al. (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, et al. (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, et al. (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

• LAG3+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• LAG-3: Identification & Validation Of Next Generation Checkpoint Pathway by Frédéric Triebel March 22, 2018

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