Cutting Edge: Molecular Analysis of the Negative Regulatory Function of Lymphocyte Activation Gene-3
Abstract
Lymphocyte activation gene (LAG)-3 (CD223) is a CD4-related activation-induced cell surface molecule that binds to MHC class II molecules with high affinity and negatively regulates T cell expansion and homeostasis. In this study, we show that LAG-3 inhibits CD4-dependent, but not CD4-independent, T cell function via its cytoplasmic domain. Although high affinity interaction with MHC class II molecules is essential for LAG-3 function, tailless LAG-3 does not compete with CD4 for ligand binding. A single lysine residue (K468) within a conserved "KIEELE" motif is essential for interaction with downstream signaling molecules. These data provide insight into the mechanism of action of this important T cell regulatory molecule.
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A single lysine residue (Lys468) within the KIEELE motif exerts an inhibitory effect in CD4+ T lymphocytes.
“Notably, a single lysine residue (Lys468) exerts an inhibitory effect in CD4+ T lymphocytes at 468 motifs within the KIEELE [324].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [324]
Cites
CD28/B7 SYSTEM OF T CELL COSTIMULATION
Lenschow, D. J., Walunas, T. L., & Bluestone, J. A. (1996) · Annual Review of Immunology · doi:10.1146/annurev.immunol.14.1.233 · Cited by 2,717 · see citing works
LAG-3, a novel lymphocyte activation gene closely related to CD4.
Triebel, F., Jitsukawa, S., Baixerás, E., Roman‐Roman, S., Genevée, C., Viégas-Pèquignot, E., & Hercend, T. (1990) · The Journal of Experimental Medicine · doi:10.1084/jem.171.5.1393 · Cited by 917 · see citing works
Baixerás, E., Huard, B., Miossec, C., Jitsukawa, S., Martin, M., Hercend, T., Auffray, C., Triebel, F., & Piatier‐Tonneau, D. (1992) · The Journal of Experimental Medicine · doi:10.1084/jem.176.2.327 · Cited by 397 · see citing works
Huard, B., Prigent, P., Tournier, M., Bruniquel, D., & Triebel, F. (1995) · European Journal of Immunology · doi:10.1002/eji.1830250949 · Cited by 391 · see citing works
Gronwald, R. G., Grant, F. J., Haldeman, B. A., Hart, C. E., O’Hara, P. J., Hagen, F. S., Ross, R., Bowen‐Pope, D. F., & Murray, M. J. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.10.3435 · Cited by 316 · see citing works
Characterization of the major histocompatibility complex class II binding site on LAG-3 protein
Huard, B., Mastrangeli, R., Prigent, P., Bruniquel, D., Donini, S., Tayar, N. E., Maigret, B., Dréano, M., & Triebel, F. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.11.5744 · Cited by 308 · see citing works
"Tolerosomes" are produced by intestinal epithelial cells
Karlsson, M., Lundin, S. B., Dahlgren, U. I., Kahu, H., Pettersson, I., & Telemo, E. (2001) · European Journal of Immunology · doi:10.1002/1521-4141(2001010)31:10 · Cited by 303 · see citing works
CD3/TCR complex‐associated lymphocyte activation gene‐3 molecules inhibit CD3/TCR signaling
Hannier, S., Tournier, M., Bismuth, G., & Triebel, F. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.8.4058 · Cited by 248 · see citing works
Persons, D. A., Allay, J. A., Allay, E. R., Smeyne, R. J., Ashmun, R. A., Sorrentino, B. P., & Nienhuis, A. W. (1997) · Blood · doi:10.1182/blood.v90.5.1777 · Cited by 222 · see citing works
Huard, B., Gaulard, P., Faure, F., Hercend, T., & Triebel, F. (1994) · Immunogenetics · doi:10.1007/bf00241263 · Cited by 202 · see citing works
Carson, R. T., Vignali, K. M., Woodland, D. L., & Vignali, D. A. A. (1997) · Immunity · doi:10.1016/s1074-7613(00)80360-x · Cited by 175 · see citing works
Self-citationIndependent Modes of Natural Killing Distinguished in Mice Lacking Lag3
Miyazaki, T., Dierich, A., Benoist, C. O., & Mathis, D. J. (1996) · Science · doi:10.1126/science.272.5260.405 · Cited by 173 · see citing works
Huard, B., Prigent, P., Pagès, F., Bruniquel, D., & Triebel, F. (1996) · European Journal of Immunology · doi:10.1002/eji.1830260533 · Cited by 132 · see citing works
Arnold, P. Y., Gruta, N. L. L., Miller, T. J., Vignali, K. M., Adams, P. S., Woodland, D. L., & Vignali, D. A. A. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.2.739 · Cited by 121 · see citing works
Self-citationVignali, D. A. A., & Strominger, J. L. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.179.6.1945 · Cited by 103 · see citing works
Self-citationAllen, P. M., McKEAN, D. J., Beck, B. N., Sheffield, J. B., & Glimcher, L. H. (1985) · The Journal of Experimental Medicine · doi:10.1084/jem.162.4.1264 · Cited by 82 · see citing works
Persons, D. A., Mehaffey, M. G., Kaleko, M., Nienhuis, A. W., & Vanin, E. F. (1998) · Blood Cells Molecules and Diseases · doi:10.1006/bcmd.1998.0184 · Cited by 81 · see citing works
Takemoto, Y., Furuta, M., Li, X., Strong-Sparks, W. J., & Hashimoto, Y. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07346.x · Cited by 79 · see citing works
Hannier, S., & Triebel, F. (1999) · International Immunology · doi:10.1093/intimm/11.11.1745 · Cited by 72 · see citing works
Mouse CD4 binds MHC class II with extremely low affinity
Weber, S., & Karjalainen, K. (1993) · International Immunology · doi:10.1093/intimm/5.6.695 · Cited by 63 · see citing works
Vignali, D. A. A., & Vignali, K. M. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.3.1431 · Cited by 53 · see citing works
Self-citationGenomic organization of the human LAG-3/CD4 locus
Bruniquel, D., Borie, N., & Triebel, F. (1997) · Immunogenetics · doi:10.1007/s002510050332 · Cited by 47 · see citing works
Cloning of Murine LAG-3 by Magnetic Bead Bound Homologous Probes and PCR (GENE-CAPTURE PCR)
Mastrangeli, R., Micangeli, E., & Donini, S. (1996) · Analytical Biochemistry · doi:10.1006/abio.1996.0382 · Cited by 43 · see citing works
Fukamachi, H., Yamada, N., Miura, T., Kato, T., Ishikawa, M., Gulbins, E., Altman, A., Kawakami, Y., & Kawakami, T. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.152.2.642 · Cited by 42 · see citing works
Arnold, P. Y., Vignali, K. M., Miller, T. B., Gruta, N. L. L., Cauley, L. S., Haynes, L., Adams, P. S., Swain, S. L., Woodland, D. L., & Vignali, D. A. A. (2002) · Journal of Immunological Methods · doi:10.1016/s0022-1759(02)00343-5 · Cited by 28 · see citing works
Self-citationPhenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3)
(2002) · doi:10.1002/1521-4141(200208)32:8
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Woo, S.-R., Turnis, M. E., Goldberg, M. V., Bankoti, J., Selby, M., Nirschl, C. J., Bettini, M. L., Gravano, D. M., Vogel, P., Liu, C. L., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-1620 · Cited by 1,647 · see citing works
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Andrews, L. P., Marciscano, A., Drake, C., & Vignali, D. A. A. (2017) · Immunological Reviews · doi:10.1111/imr.12519 · Cited by 881 · see citing works
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Li, N., Wang, Y., Forbes, K., Vignali, K. M., Heale, B. S. E., Säftig, P., Hartmann, D., Black, R. A., Rossi, J. J., Blobel, C., et al. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601520 · Cited by 282 · see citing works
Self-citationMaruhashi, T., Okazaki, I.-M., Sugiura, D., Takahashi, S., Maeda, T. K., Shimizu, K., & Okazaki, T. (2018) · Nature Immunology · doi:10.1038/s41590-018-0217-9 · Cited by 275 · see citing works
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Kisielow, M., Kisielow, J., Sollami, G., & Karjalainen, K. (2005) · European Journal of Immunology · doi:10.1002/eji.200526090 · Cited by 271 · see citing works
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Chocarro, L., Blanco, E., Zuazo, M., Arasanz, H., Bocanegra, A., Fernández, L., Morente, P., Fernández-Hinojal, G., Echaide, M., Garnica, M., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105282 · Cited by 217 · see citing works
Guy, C. S., Mitrea, D. M., Chou, P.-C., Temirov, J. P., Vignali, K. M., Liu, X., Zhang, H., Kriwacki, R. W., Bruchez, M. P., Watkins, S. C., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01176-4 · Cited by 214 · see citing works
Self-citationPentcheva‐Hoang, T., Corse, E., & Allison, J. P. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00763.x · Cited by 202 · see citing works
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Ye, L., Park, J. J.-Y., Dong, M. B., Yang, Q., Chow, R. D.-W., Peng, L., Du, Y., Guo, J., Dai, X., Wang, G., et al. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0246-4 · Cited by 199 · see citing works
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Maçon‐Lemaître, L., & Triebel, F. (2005) · Immunology · doi:10.1111/j.1365-2567.2005.02145.x · Cited by 192 · see citing works
Rotger, M., Dalmau, J., Rauch, A., McLaren, P. J., Bosinger, S. E., Martínez, R., Utay, N. S., Roque, A., Liebner, J. C., Battegay, M., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45235 · Cited by 188 · see citing works
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Shi, A., Tang, X., Xiong, Y., Zheng, K., Liu, Y., Shi, X.-G., Lv, Y., Jiang, T., Ma, N., & Zhao, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.785091 · Cited by 186 · see citing works
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Durham, N. M., Nirschl, C. J., Jackson, C. M., Elias, J., Kochel, C. M., Anders, R. A., & Drake, C. G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0109080 · Cited by 178 · see citing works
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Checkpoint inhibitors in hematological malignancies
Ok, C. Y., & Young, K. H. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0474-3 · Cited by 136 · see citing works
Joller, N., & Kuchroo, V. K. (2017) · Current topics in microbiology and immunology · doi:10.1007/82_2017_62 · Cited by 138 · see citing works
Molecular Pathways and Mechanisms of LAG3 in Cancer Therapy
Andrews, L. P., Cillo, A. R., Karapetyan, L., Kirkwood, J. M., Workman, C. J., & Vignali, D. A. A. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2390 · Cited by 122 · see citing works
Self-citationKlümper, N., Ralser, D. J., Bawden, E., Landsberg, J., Zarbl, R., Kristiansen, G., Toma, M. I., Ritter, M., Hölzel, M., Ellinger, J., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000552 · Cited by 116 · see citing works
IELs: enforcing law and order in the court of the intestinal epithelium
Cheroutre, H. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00284.x · Cited by 117 · see citing works
The CD4-like molecule LAG-3, biology and therapeutic applications
Sierro, S. R., Romero, P. J., & Speiser, D. E. (2010) · Expert Opinion on Therapeutic Targets · doi:10.1517/14712598.2011.540563 · Cited by 115 · see citing works
Maeda, T. K., Sugiura, D., Okazaki, I., Maruhashi, T., & Okazaki, T. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007455 · Cited by 115 · see citing works
Targeting Checkpoint Receptors and Molecules for Therapeutic Modulation of Natural Killer Cells
Kim, N., & Kim, H. S. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02041 · Cited by 110 · see citing works
Bae, J., Lee, S. J., Park, C., Lee, Y. S., & Chun, T. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401025 · Cited by 106 · see citing works
Deshpande, R. P., Sharma, S., & Watabe, K. (2020) · Cancers · doi:10.3390/cancers12102983 · Cited by 101 · see citing works
PD-L1/LAG-3 bispecific antibody enhances tumor-specific immunity
Jiang, H., Ni, H., Zhang, P., Guo, X., Wu, M., Shen, H., Wang, J., Wu, W., Wu, Z., Ding, J., et al. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1943180 · Cited by 99 · see citing works
Clinical landscape of LAG-3-targeted therapy
Chocarro, L., Blanco, E., Arasanz, H., Fernández, L., Bocanegra, A., Echaide, M., Garnica, M., Ramos, P., Fernández-Hinojal, G., Vera, R., et al. (2022) · Immuno-Oncology Technology · doi:10.1016/j.iotech.2022.100079 · Cited by 98 · see citing works
Newly Emerging Immune Checkpoints: Promises for Future Cancer Therapy
Torphy, R. J., Schulick, R. D., & Zhu, Y. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122642 · Cited by 98 · see citing works
CD8 + T cell exhaustion in anti‐tumour immunity: The new insights for cancer immunotherapy
Huang, Y., Jia, A., Wang, Y., & Liu, G. (2022) · Immunology · doi:10.1111/imm.13588 · Cited by 95 · see citing works
Targeting the NF-κB pathway as a potential regulator of immune checkpoints in cancer immunotherapy
Ebrahimi, N., Abdulwahid, A. R. R., Mansouri, A., Karimi, N., Bostani, R. J., Beiranvand, S., Adelian, S., Khorram, R., Vafadar, R., Hamblin, M. R., et al. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-05098-8 · Cited by 98 · see citing works
Negative immune checkpoints on T lymphocytes and their relevance to cancer immunotherapy
Śledzińska, A., Menger, L., Bergerhoff, K. F., Peggs, K. S., & Quezada, S. A. (2015) · Molecular Oncology · doi:10.1016/j.molonc.2015.10.008 · Cited by 93 · see citing works
LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition
Ming, Q., Celias, D. P., Wu, C., Cole, A. R., Singh, S., Mason, C. C., Dong, S., Tran, T. H., Amarasinghe, G. K., Ruffell, B., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01238-7 · Cited by 92 · see citing works
Immune checkpoint molecules in pregnancy: Focus on regulatory T cells
Zhang, Y., & Sun, H. (2020) · European Journal of Immunology · doi:10.1002/eji.201948382 · Cited by 91 · see citing works
Bayry, J., Triebel, F., Kaveri, S. V., & Tough, D. F. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.7.4184 · Cited by 91 · see citing works
Javadrashid, D., Baghbanzadeh, A., Derakhshani, A., Leone, P., Silvestris, N., Racanelli, V., Solimando, A. G., & Baradaran, B. (2021) · Biomedicines · doi:10.3390/biomedicines9040373 · Cited by 87 · see citing works
Tumor Immunology and Immunotherapy of Non-Small-Cell Lung CancerPreprint
Cascone, T., Fradette, J. J., Pradhan, M., & Gibbons, D. L. (2021) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a037895 · Cited by 85 · see citing works
Differential subcellular localization of the regulatory T‐cell protein LAG‐3 and the coreceptor CD4
Woo, S., Li, N., Bruno, T. C., Forbes, K., Brown, S. A., Workman, C. J., Drake, C. G., & Vignali, D. A. A. (2010) · European Journal of Immunology · doi:10.1002/eji.200939874 · Cited by 83 · see citing works
Self-citationMechanisms of Action of Regulatory T Cells Specific for Paternal Antigens During Pregnancy
Schumacher, A., Wafula, P. O., Bertoja, A. Z., Sollwedel, A., Thuere, C., Wollenberg, I., Yagita∥, H., Volk, H., & Zenclussen, A. C. (2007) · Obstetrics and Gynecology · doi:10.1097/01.aog.0000284625.10175.31 · Cited by 79 · see citing works
Control of NK Cell Activation by Immune Checkpoint Molecules
Beldi‐Ferchiou, A., & Caillat‐Zucman, S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102129 · Cited by 77 · see citing works
Li, Q., Schacker, T. W., Carlis, J. V., Beilman, G. J., Nguyen, P. L., & Haase, A. T. (2004) · The Journal of Infectious Diseases · doi:10.1086/381396 · Cited by 76 · see citing works
News on immune checkpoint inhibitors as immunotherapy strategies in adult and pediatric solid tumors
Melaiu, O., Lucarini, V., Giovannoni, R., Fruci, D., & Gemignani, F. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.07.001 · Cited by 75 · see citing works
Jiang, Y., Dai, A., Huang, Y., Li, H., Cui, J., Yang, H., Si, L., Jiao, T., Ren, Z., Zhang, Z., et al. (2025) · Cell · doi:10.1016/j.cell.2025.02.014 · Cited by 74 · see citing works
Self-citationRoles of LAG3 and EGR2 in regulatory T cells
Okamura, T., Fujio, K., Sumitomo, S., & Yamamoto, K. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2011-200588 · Cited by 74 · see citing works
Rudd, C. E., Chanthong, K., & Taylor, A. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.076 · Cited by 72 · see citing works
Targeted Anti‐Tumor Immunotherapy Using Tumor Infiltrating Cells
Xie, Y., Xie, F., Zhang, L., Zhou, X., Huang, J., Wang, F., Jin, J., Zhang, L., Zeng, L., & Zhou, F. (2021) · Advanced Science · doi:10.1002/advs.202101672 · Cited by 71 · see citing works
Soluble Human LAG-3 Molecule Amplifies the In vitro Generation of Type 1 Tumor-Specific Immunity
Casati, C., Camisaschi, C., Rini, F., Arienti, F., Rivoltini, L., Triebel, F., Parmiani, G., & Castelli, C. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2728 · Cited by 72 · see citing works
Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy
Chrétien, S., Zerdes, I., Bergh, J. C. S., Matikas, A., & Foukakis, T. (2019) · Cancers · doi:10.3390/cancers11050628 · Cited by 70 · see citing works
- Authors
- Workman, C. J., Dugger, K. J., & Vignali, D. A. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-11
- Volume
- 169
- Issue
- 10
- Pages
- 5392-5395
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1480698358
- Cited by
- 389
- References
- 26
- Citations by year
- 2026: 18 · 2025: 28 · 2024: 50 · 2023: 41 · 2022: 37 · 2021: 30 · 2020: 38 · 2019: 30 · 2018: 25 · 2017: 17 · 2016: 9 · 2015: 12 · 2014: 3 · 2013: 4 · 2012: 7
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA-09346, T32CA009346, CA23944, CA21765, R25CA023944, P30CA021765)
- National Institute of Allergy and Infectious Diseases (T32AI007372, AI-07372, AI39480)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- LAG-3, T cell regulation, MHC class II binding, cytoplasmic domain, negative regulation of T cell activation
- MeSH terms
- Lymphocyte Activation Gene 3 Protein, Amino Acid Sequence, Animals, Histocompatibility Antigens Class II, Cytoplasm, Humans, Hybridomas, Ligands, Lymphocyte Activation, Membrane Proteins, Molecular Sequence Data, Tumor Cells, Cultured, Down-Regulation, Antigens, CD, CD4 Antigens, Conserved Sequence, Protein Structure, Tertiary, Amino Acid Motifs, Mice
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