LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation.

Antigens, CD / immunology CD3 Complex / immunology CD8 Antigens / metabolism CD8-Positive T-Lymphocytes Histocompatibility Antigens Class II Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism Receptors, Antigen, T-Cell / metabolism Signal Transduction Lymphocyte Activation Gene 3 Protein

Journal

Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354

Informations de publication

Date de publication:
05 2022
Historique:
received: 22 10 2020
accepted: 03 03 2022
pubmed: 20 4 2022
medline: 20 5 2022
entrez: 19 4 2022
Statut: ppublish

Résumé

LAG3 is an inhibitory receptor that is highly expressed on exhausted T cells. Although LAG3-targeting immunotherapeutics are currently in clinical trials, how LAG3 inhibits T cell function remains unclear. Here, we show that LAG3 moved to the immunological synapse and associated with the T cell receptor (TCR)-CD3 complex in CD4

Identifiants

DOI: 10.1038/s41590-022-01176-4 PMID: 35437325 PMC: PMC9106921
pubmed: 35437325
doi: 10.1038/s41590-022-01176-4
pii: 10.1038/s41590-022-01176-4
pmc: PMC9106921
mid: NIHMS1792750
doi:

Substances chimiques

Antigens, CD 0
CD3 Complex 0
CD8 Antigens 0
Histocompatibility Antigens Class II 0
Receptors, Antigen, T-Cell 0
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) EC 2.7.10.2
Lymphocyte Activation Gene 3 Protein 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

757-767

Subventions

Organisme : NIAID NIH HHS
ID : P01 AI108545
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA047904
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI129893
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI144422
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Références

Andrews, L. P., Marciscano, A. E., Drake, C. G. & Vignali, D. A. LAG3 (CD223) as a cancer immunotherapy target. Immunol. Rev. 276, 80–96 (2017).
pubmed: 28258692 pmcid: 5338468 doi: 10.1111/imr.12519
Maruhashi, T., Sugiura, D., Okazaki, I. M. & Okazaki, T. LAG-3: from molecular functions to clinical applications. J. Immunother. Cancer 8, e001014 (2020).
pubmed: 32929051 pmcid: 7488795 doi: 10.1136/jitc-2020-001014
Ruffo, E., Wu, R. C., Bruno, T. C., Workman, C. J. & Vignali, D. A. A. Lymphocyte-activation gene 3 (LAG3): the next immune checkpoint receptor. Semin. Immunol. 42, 101305 (2019).
pubmed: 31604537 pmcid: 6920665 doi: 10.1016/j.smim.2019.101305
Huard, B. et al. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc. Natl Acad. Sci. USA 94, 5744–5749 (1997).
pubmed: 9159144 pmcid: 20850 doi: 10.1073/pnas.94.11.5744
Workman, C. J. & Vignali, D. A. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J. Immunol. 174, 688–695 (2005).
pubmed: 15634887 doi: 10.4049/jimmunol.174.2.688
Workman, C. J. & Vignali, D. A. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur. J. Immunol. 33, 970–979 (2003).
pubmed: 12672063 doi: 10.1002/eji.200323382
Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).
pubmed: 22186141 doi: 10.1158/0008-5472.CAN-11-1620
Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).
pubmed: 19043418 doi: 10.1038/ni.1679
Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).
pubmed: 21739672 doi: 10.1038/ni.2035
Workman, C. J., Dugger, K. J. & Vignali, D. A. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J. Immunol. 169, 5392–5395 (2002).
pubmed: 12421911 doi: 10.4049/jimmunol.169.10.5392
Maeda, T. K., Sugiura, D., Okazaki, I. M., Maruhashi, T. & Okazaki, T. Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. J. Biol. Chem. 294, 6017–6026 (2019).
pubmed: 30760527 pmcid: 6463702 doi: 10.1074/jbc.RA119.007455
Baixeras, E. et al. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J. Exp. Med. 176, 327–337 (1992).
pubmed: 1380059 doi: 10.1084/jem.176.2.327
Grebinoski, S. & Vignali, D. A. Inhibitory receptor agonists: the future of autoimmune disease therapeutics? Curr. Opin. Immunol. 67, 1–9 (2020).
pubmed: 32619929 pmcid: 7744338 doi: 10.1016/j.coi.2020.06.001
Szent-Gyorgyi, C. et al. Fluorogen-activating single-chain antibodies for imaging cell surface proteins. Nat. Biotechnol. 26, 235–240 (2008).
pubmed: 18157118 doi: 10.1038/nbt1368
Perkins, L. A. et al. High-content surface and total expression siRNA kinase library screen with VX-809 treatment reveals kinase targets that enhance F508del-CFTR rescue. Mol. Pharm. 15, 759–767 (2018).
pubmed: 29384380 pmcid: 5844356 doi: 10.1021/acs.molpharmaceut.7b00928
Samir, P. et al. DDX3X acts as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome. Nature 573, 590–594 (2019).
pubmed: 31511697 pmcid: 6980284 doi: 10.1038/s41586-019-1551-2
Fu, G. et al. Metabolic control of TFH cells and humoral immunity by phosphatidylethanolamine. Nature 595, 724–729 (2021).
pubmed: 34234346 pmcid: 8448202 doi: 10.1038/s41586-021-03692-z
Chen, F., Tillberg, P. W. & Boyden, E. S. Optical imaging. Expansion microscopy. Science 347, 543–548 (2015).
pubmed: 25592419 pmcid: 4312537 doi: 10.1126/science.1260088
Wassie, A. T., Zhao, Y. & Boyden, E. S. Expansion microscopy: principles and uses in biological research. Nat. Methods 16, 33–41 (2019).
pubmed: 30573813 doi: 10.1038/s41592-018-0219-4
Huang, W. Y. C., Ditlev, J. A., Chiang, H. K., Rosen, M. K. & Groves, J. T. Allosteric modulation of Grb2 recruitment to the intrinsically disordered scaffold protein, LAT, by remote site phosphorylation. J. Am. Chem. Soc. 139, 18009–18015 (2017).
pubmed: 29182244 pmcid: 5761276 doi: 10.1021/jacs.7b09387
Bettini, M. et al. Cutting edge: accelerated autoimmune diabetes in the absence of LAG-3. J. Immunol. 187, 3493–3498 (2011).
pubmed: 21873518 doi: 10.4049/jimmunol.1100714
Huang, C. T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).
pubmed: 15485628 doi: 10.1016/j.immuni.2004.08.010
Woo, S. R. et al. Differential subcellular localization of the regulatory T-cell protein LAG-3 and the coreceptor CD4. Eur. J. Immunol. 40, 1768–1777 (2010).
pubmed: 20391435 pmcid: 2987677 doi: 10.1002/eji.200939874
Workman, C. J. et al. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J. Immunol. 172, 5450–5455 (2004).
pubmed: 15100286 doi: 10.4049/jimmunol.172.9.5450
Grosso, J. F. et al. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J. Immunol. 182, 6659–6669 (2009).
pubmed: 19454660 doi: 10.4049/jimmunol.0804211
Grosso, J. F. et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J. Clin. Invest. 117, 3383–3392 (2007).
pubmed: 17932562 pmcid: 2000807 doi: 10.1172/JCI31184
Veillette, A., Bookman, M. A., Horak, E. M. & Bolen, J. B. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase Lck. Cell 55, 301–308 (1988).
pubmed: 3262426 doi: 10.1016/0092-8674(88)90053-0
Rudd, C. E., Trevillyan, J. M., Dasgupta, J. D., Wong, L. L. & Schlossman, S. F. The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. Proc. Natl Acad. Sci. USA 85, 5190–5194 (1988).
pubmed: 2455897 pmcid: 281714 doi: 10.1073/pnas.85.14.5190
Horkova, V. et al. Dynamics of the coreceptor-LCK interactions during T cell development shape the self-reactivity of peripheral CD4 and CD8 T cells. Cell Rep. 30, 1504–1514 e1507 (2020).
pubmed: 32023465 doi: 10.1016/j.celrep.2020.01.008
Kim, P. W., Sun, Z. Y., Blacklow, S. C., Wagner, G. & Eck, M. J. A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8. Science 301, 1725–1728 (2003).
pubmed: 14500983 doi: 10.1126/science.1085643
Alberts, I. L., Nadassy, K. & Wodak, S. J. Analysis of zinc binding sites in protein crystal structures. Protein Sci. 7, 1700–1716 (1998).
pubmed: 10082367 pmcid: 2144076 doi: 10.1002/pro.5560070805
Rigo, A. et al. Interaction of copper with cysteine: stability of cuprous complexes and catalytic role of cupric ions in anaerobic thiol oxidation. J. Inorg. Biochem. 98, 1495–1501 (2004).
pubmed: 15337601 doi: 10.1016/j.jinorgbio.2004.06.008
Lee, K. H. et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167, 774–788 e717 (2016).
pubmed: 27768896 pmcid: 5079111 doi: 10.1016/j.cell.2016.10.002
Mitrea, D. M. & Kriwacki, R. W. Phase separation in biology; functional organization of a higher order. Cell Commun. Signal 14, 1 (2016).
pubmed: 26727894 pmcid: 4700675 doi: 10.1186/s12964-015-0125-7
Storch, S., Pohl, S. & Braulke, T. A dileucine motif and a cluster of acidic amino acids in the second cytoplasmic domain of the batten disease-related CLN3 protein are required for efficient lysosomal targeting. J. Biol. Chem. 279, 53625–53634 (2004).
pubmed: 15469932 doi: 10.1074/jbc.M410930200
Johnson, A. O., Lampson, M. A. & McGraw, T. E. A di-leucine sequence and a cluster of acidic amino acids are required for dynamic retention in the endosomal recycling compartment of fibroblasts. Mol. Biol. Cell 12, 367–381 (2001).
pubmed: 11179421 pmcid: 30949 doi: 10.1091/mbc.12.2.367
Uversky, V. N. The alphabet of intrinsic disorder: II. Various roles of glutamic acid in ordered and intrinsically disordered proteins. Intrinsically Disord. Proteins 1, e24684 (2013).
pubmed: 28516010 pmcid: 5424795 doi: 10.4161/idp.24684
Miyazaki, T., Dierich, A., Benoist, C. & Mathis, D. Independent modes of natural killing distinguished in mice lacking Lag3. Science 272, 405–408 (1996).
pubmed: 8602528 doi: 10.1126/science.272.5260.405
Kaye, J. et al. Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature 341, 746–749 (1989).
pubmed: 2571940 doi: 10.1038/341746a0
Singh, S. K. et al. Mapping the interaction between the cytoplasmic domains of HIV-1 viral protein U and human CD4 with NMR spectroscopy. FEBS J. 279, 3705–3714 (2012).
pubmed: 22863293 doi: 10.1111/j.1742-4658.2012.08732.x
Huppa, J. B. et al. TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity. Nature 463, 963–967 (2010).
pubmed: 20164930 pmcid: 3273423 doi: 10.1038/nature08746
Kaizuka, Y., Douglass, A. D., Varma, R., Dustin, M. L. & Vale, R. D. Mechanisms for segregating T cell receptor and adhesion molecules during immunological synapse formation in Jurkat T cells. Proc. Natl Acad. Sci. USA 104, 20296–20301 (2007).
pubmed: 18077330 pmcid: 2154425 doi: 10.1073/pnas.0710258105
Liedmann, S. et al. Viral suppressors of the RIG-I-mediated interferon response are pre-packaged in influenza virions. Nat. Commun. 5, 5645 (2014).
pubmed: 25487526 doi: 10.1038/ncomms6645
Bates, M., Huang, B., Dempsey, G. T. & Zhuang, X. Multicolor super-resolution imaging with photo-switchable fluorescent probes. Science 317, 1749–1753 (2007).
pubmed: 17702910 pmcid: 2633025 doi: 10.1126/science.1146598
Keller, R. The Computer Aided Resonance Assignment 1st edn (CANTINA, 2004).
Santoro, M. M. & Bolen, D. W. Unfolding free energy changes determined by the linear extrapolation method. 1. Unfolding of phenylmethanesulfonyl alpha-chymotrypsin using different denaturants. Biochemistry 27, 8063–8068 (1988).
pubmed: 3233195 doi: 10.1021/bi00421a014

Auteurs

Clifford Guy (C)

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Diana M Mitrea (DM)

Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Dewpoint Therapeutics, Boston, MA, USA.

Po-Chien Chou (PC)

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Jamshid Temirov (J)

Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Kate M Vignali (KM)

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Xueyan Liu (X)

Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Mathematics, University of New Orleans, New Orleans, LA, USA.

Hui Zhang (H)

Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Division of Biostatistics, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
ORCID: 0000-0001-6825-5649

Richard Kriwacki (R)

Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN, USA.
ORCID: 0000-0002-9798-6018

Marcel P Bruchez (MP)

Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, USA.
Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, PA, USA.
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.

Simon C Watkins (SC)

Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
ORCID: 0000-0003-4092-1552

Creg J Workman (CJ)

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. cworkman@pitt.edu.
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. cworkman@pitt.edu.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. cworkman@pitt.edu.
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. cworkman@pitt.edu.
ORCID: 0000-0002-9964-9509

Dario A A Vignali (DAA)

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. dvignali@pitt.edu.
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. dvignali@pitt.edu.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. dvignali@pitt.edu.
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. dvignali@pitt.edu.
Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. dvignali@pitt.edu.
ORCID: 0000-0002-2771-5992

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Classifications MeSH

questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes CD › LAG3 associates with TCR-CD3 complexes and...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes de différenciation des lymphocytes T › Antigènes CD3 › LAG3 associates with TCR-CD3 complexes and...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes de différenciation des lymphocytes T › Antigènes CD8 › LAG3 associates with TCR-CD3 complexes and...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Lymphocytes T CD8+ › LAG3 associates with TCR-CD3 complexes and...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Isoantigènes › Antigènes d'histocompatibilité › Antigènes d'histocompatibilité de classe II › LAG3 associates with TCR-CD3 complexes and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéine tyrosine kinase p56(lck) spécifique des lymphocytes › LAG3 associates with TCR-CD3 complexes and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs aux antigènes › Récepteurs aux antigènes des cellules T › LAG3 associates with TCR-CD3 complexes and...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › LAG3 associates with TCR-CD3 complexes and...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes de différenciation des lymphocytes T › Protéine LAG-3 › LAG3 associates with TCR-CD3 complexes and...