Affinage

LAG3

Lymphocyte activation gene 3 protein · UniProt P18627

Length
525 aa
Mass
57.4 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LAG3 (CD223) is an inhibitory co-receptor that restrains T cell activation, controls T cell homeostasis and the size of the memory pool, and supports the suppressive function of regulatory T cells (PMID:35437325, PMID:15100286, PMID:28783703). Upon recruitment to the immunological synapse, LAG3 associates with the TCR-CD3 complex independently of MHC class II, a step requiring LAG3 dimerization, and delivers inhibitory signals through its cytoplasmic tail (PMID:35437325, PMID:38775415). Mechanistically, an acidic tandem glutamic acid-proline repeat lowers local synapse pH to dissociate Lck from the CD4/CD8 co-receptor, while LAG3 also forms condensates with CD3ε via an intracellular FSAL motif to disrupt CD3ε/Lck association, with cognate peptide-MHC class II proximity to the TCR being required for optimal suppression (PMID:35437325, PMID:40592325). Ligand engagement triggers c-Cbl/Cbl-b-mediated non-K48 polyubiquitination that releases the membrane-bound juxtamembrane basic sequence, stabilizing the tail in a signaling-competent conformation; this ubiquitination is required for suppression of antitumor immunity (PMID:40101708). Stable peptide-MHC class II is the functional ligand for both autoimmunity and anti-cancer immunity, with FGL1 serving as an MHC-class-II-independent ligand whose cross-linking drives higher-order LAG3 oligomerization; the ectodomain dimerizes through Ig domain 2, with a domain-1 loop 2 region engaging both ligands (PMID:35761082, PMID:30580966, PMID:35413245). On Foxp3+ Tregs, LAG3 limits proliferation and metabolic activity by restraining Myc and PI3K-Akt-Rictor signaling and mediates contact-dependent suppression of antigen-presenting cells via MHC class II (PMID:28783703, PMID:39236718, PMID:30097293). LAG3 is proteolytically cleaved by ADAM10/ADAM17 to release a soluble ectodomain that engages MHC class II on dendritic cells to drive their maturation and signaling (PMID:15557174, PMID:11937541, PMID:38026700).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2002 High

    Established that soluble LAG-3 acts as an MHC class II ligand on dendritic cells, defining a function for LAG3 beyond T-cell-intrinsic inhibition.

    Evidence LAG-3Ig fusion protein treatment of human monocyte-derived DCs with morphology, surface marker, cytokine, and T cell priming readouts

    PMID:11937541

    Open questions at the time
    • Did not define the LAG3 cytoplasmic signaling mechanism
    • Effects shown with soluble fusion protein rather than endogenous cleaved sLAG-3
  2. 2003 High

    Identified the cytoplasmic determinant of LAG3 inhibitory signaling, showing a conserved KIEELE motif is essential for regulating T cell expansion.

    Evidence Retroviral reconstitution of wild-type and cytoplasmic mutants in LAG-3−/− T cells with expansion assays; parallel DC studies dissecting MHC-class-II signaling pathways

    PMID:12547595 PMID:12672063 PMID:12775570

    Open questions at the time
    • Downstream effectors of the KIEELE motif not identified at the time
    • Did not connect motif to TCR-CD3 association
  3. 2004 High

    Showed LAG-3 negatively regulates T cell expansion and memory pool size in vivo, and that it is proteolytically processed to release a soluble ectodomain.

    Evidence LAG-3−/− mice with superantigen and viral infection models; biochemical fractionation and domain-deletion mapping of cleavage fragments

    PMID:15100286 PMID:15557174

    Open questions at the time
    • Protease responsible for cleavage not identified in these studies
    • Molecular mechanism of inhibition still unresolved
  4. 2005 High

    Linked LAG3 to homeostatic T cell control and lipid-raft synapse localization, and extended sLAG-3 effects to monocyte differentiation.

    Evidence LAG-3−/− mice with adoptive transfer; confocal co-localization with CD3/CD4/CD8 in lipid rafts; sLAG-3 treatment of human monocytes

    PMID:15634887 PMID:15720438 PMID:15885122

    Open questions at the time
    • Co-localization data (Medium) not mechanistically dissected
    • Treg dependence on LAG3 shown functionally but molecular basis unknown
  5. 2017 High

    Defined a Treg-intrinsic role: LAG3 limits Treg proliferation and function at inflammatory sites by restraining IL-2-STAT5 signaling.

    Evidence Treg-specific conditional knockout (Foxp3-Cre x Lag3-flox), RNA-seq of intra-islet Tregs, competition transfers, STAT5 phosphorylation assays

    PMID:28783703

    Open questions at the time
    • How LAG3 signaling links to STAT5 restraint not resolved
    • Site-specific competitive advantage mechanism unclear
  6. 2018 High

    Identified FGL1 as a major MHC-class-II-independent functional ligand and established contact-dependent Treg suppression of APCs through MHC class II.

    Evidence FGL1 binding assays, blocking antibodies, FGL1 KO mice, tumor models; Treg-macrophage co-culture with LAG-3 blockade and colitis model

    PMID:30005826 PMID:30097293 PMID:30580966

    Open questions at the time
    • Relative contributions of FGL1 versus pMHCII not yet ranked
    • Receptor conformational consequences of ligand binding unknown
  7. 2022 High

    Provided the structural and signaling framework: ectodomain dimerization via Ig domain 2, ligand-induced oligomerization, TCR-CD3 association requiring dimerization, and a pH/Lck-dissociation mechanism in the cytoplasmic tail.

    Evidence Crystallography and cryo-EM with interface mutagenesis; dimerization-defective mutants with reciprocal Co-IP and tumor models; Co-IP, live imaging, pH reporters and functional T cell assays

    PMID:35437325 PMID:35761082 PMID:38775415

    Open questions at the time
    • How dimerization and the acidic E-P repeat are coordinated in time not fully resolved
    • Stoichiometry of LAG3-TCR-CD3 assembly at the synapse not defined
  8. 2022 High

    Resolved which ligand drives suppression, showing stable pMHCII binding is the functional ligand for both autoimmunity and anti-cancer immunity.

    Evidence In vitro suppression assays with binding mutants and knock-in mice in NOD diabetes and tumor models

    PMID:35413245

    Open questions at the time
    • Reconciliation with FGL1 ligand activity not fully integrated
    • Whether different ligands trigger distinct signaling outputs unresolved
  9. 2024 High

    Distinguished LAG3 from other checkpoints in exhausted T cells and detailed Treg metabolic control by LAG3.

    Evidence LAG-3/PD-1 single and double KO mice in chronic LCMV with TOX and cytotoxicity readouts; Treg-specific Lag3 mutants with transcriptomics, metabolomics, and PI3K/Rictor/Ldha inhibitor rescue

    PMID:39121847 PMID:39236718

    Open questions at the time
    • How a single inhibitory receptor selectively shapes effector function versus proliferation not mechanistically defined
    • Link between membrane signaling and Myc/metabolic restraint not established
  10. 2025 High

    Completed the proximal signaling model: ligand-induced c-Cbl/Cbl-b ubiquitination releases the juxtamembrane tail for signaling, and CD3ε condensate formation via FSAL disrupts CD3ε/Lck.

    Evidence Ubiquitination assays, E3 ligase identification, juxtamembrane mutagenesis, in vivo tumor models and patient cohorts; proximity ligation, super-resolution imaging, FSAL mutagenesis, bispecific antibody rescue, autoimmune models

    PMID:40101708 PMID:40592325

    Open questions at the time
    • Integration of ubiquitination, pH-Lck dissociation, and CD3ε condensation into one ordered pathway not yet formalized
    • Generality across CD4 versus CD8 T cells partially addressed
  11. 2024 Medium

    Explored a non-immune role in neurodegeneration, with conflicting evidence on LAG3 as a mediator of pathologic α-synuclein uptake.

    Evidence Aplp1-Lag3 Co-IP, double-KO mice and anti-Lag3 blockade in α-syn PFF model; contrasted with prior reports of no neuronal LAG3 expression or functional effect, and IFN-γ/STAT1-induced microglial LAG3

    PMID:34309222 PMID:38026700 PMID:38821932

    Open questions at the time
    • Conflicting reports on whether LAG3 contributes to α-synuclein pathology not reconciled
    • Cell type expressing functionally relevant LAG3 in brain disputed
    • Mechanism of Aplp1-Lag3 cooperation in fibril internalization incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct proximal mechanisms (acidic E-P repeat-driven Lck dissociation, FSAL-CD3ε condensation, Cbl-mediated ubiquitination) are temporally ordered and whether they operate in parallel or sequentially during a single inhibitory event remains unresolved.
  • No unified kinetic model linking the three cytoplasmic mechanisms
  • Relative ligand-specific contributions of pMHCII versus FGL1 to each step not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
APLP1CBLCBLBCD3EFGL1

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 LAG3 moves to the immunological synapse and associates with the TCR-CD3 complex in CD4+ and CD8+ T cells independently of MHC class II binding. A phylogenetically conserved acidic tandem glutamic acid-proline repeat in the LAG3 cytoplasmic tail lowers pH at the immune synapse and causes dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor, resulting in loss of co-receptor-TCR signaling and limited T cell activation. Co-immunoprecipitation, live-cell imaging, pH-sensing reporters, mutational analysis of cytoplasmic domain, functional T cell activation assays Nature immunology High 35437325
2025 LAG3 undergoes robust non-K48-linked polyubiquitination upon engagement of MHC class II or membrane-bound (but not soluble) FGL1. This ubiquitination, mediated redundantly by E3 ligases c-Cbl and Cbl-b, disrupts membrane binding of the juxtamembrane basic residue-rich sequence, stabilizing the LAG3 cytoplasmic tail in a membrane-dissociated conformation that enables inhibitory signaling. LAG3 ubiquitination is required for suppression of antitumor immunity in vivo, and therapeutic antibodies repress LAG3 ubiquitination. Ubiquitination assays, E3 ligase identification (c-Cbl/Cbl-b), mutagenesis of juxtamembrane domain, in vivo tumor models, patient cohort analysis Cell High 40101708
2025 LAG3's spatial proximity to the TCR (but not CD4 co-receptor), facilitated by cognate peptide-MHC class II, is required for optimal CD4+ T cell suppression. LAG3 forms condensates with TCR signaling component CD3ε through its intracellular FSAL motif, disrupting CD3ε/Lck association. MHC class II interaction alone is insufficient for optimal LAG3 function. Proximity ligation assays, super-resolution microscopy, co-immunoprecipitation, FSAL-motif mutagenesis, bispecific antibody rescue experiments, autoimmune mouse models Cell High 40592325
2022 LAG3 dimerization is required for its association with the TCR/CD3 complex and for optimal inhibitory function. A LAG3 mutant unable to dimerize shows perturbed TCR/CD3 association in CD8+ T cells and reduced inhibition in a tumor model. The therapeutic antibody C9B7W disrupts LAG3 dimerization and its TCR/CD3 association without blocking MHC class II binding. Dimerization-defective LAG3 mutant, co-immunoprecipitation with TCR/CD3, in vivo B16-gp100 tumor model, antibody epitope mapping Journal of immunology High 38775415
2022 Crystal and cryo-EM structures of human and murine LAG3 ectodomains reveal a dimeric assembly mediated by Ig domain 2. A flexible 'loop 2' region in LAG3 domain 1 is the epitope for a potent antagonist antibody that blocks both MHC class II and FGL1 interactions. FGL1 cross-linking induces higher-order LAG3 oligomers, implicating ligand-mediated clustering as a mechanism for disrupting T cell activation. X-ray crystallography, cryo-EM, mutational mapping of LAG3-FGL1 and LAG3-MHC class II interfaces, oligomerization assays Nature immunology High 35761082
2018 Fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent of MHC class II. FGL1 inhibits antigen-specific T cell activation, and blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity in mouse models. Binding assays, LAG-3/FGL1 blocking monoclonal antibodies, FGL1 knockout mice, in vivo tumor models, T cell activation assays Cell High 30580966
2022 Binding of LAG-3 to stable peptide-MHC class II (pMHCII) complexes, but not to FGL1, induces T cell suppression in vitro. LAG-3 mutants lacking stable pMHCII-binding capacity but not FGL1-binding capacity lost suppressive activity. Targeted disruption of stable pMHCII-binding of LAG-3 in NOD mice recapitulated diabetes exacerbation seen with LAG-3 deficiency, and augmented anti-cancer immunity in C57BL/6 mice, identifying stable pMHCII as the functional ligand for both autoimmunity and anti-cancer immunity. In vitro T cell suppression assays with LAG-3 binding mutants, knock-in mice with site-specific mutations, autoimmune diabetes model (NOD), tumor models Immunity High 35413245
2004 LAG-3 is proteolytically cleaved within the D4 transmembrane domain connecting peptide, producing a 54-kDa N-terminal extracellular fragment that oligomerizes with full-length LAG-3 (70 kDa) on the cell surface via the D1 domain, and a 16-kDa C-terminal fragment containing the transmembrane and cytoplasmic domains. The 54-kDa fragment is subsequently released as soluble LAG-3 (sLAG-3), a process enhanced by T cell activation in vitro and in vivo. Biochemical fractionation, Western blotting, domain-deletion mutants, in vivo serum analysis in C57BL/6 and RAG-1−/− mice Journal of immunology High 15557174
2003 LAG-3 function on T cells is mediated via its cytoplasmic domain, and a conserved 'KIEELE' motif within this domain is essential for LAG-3's regulatory activity on T cell expansion. Retroviral reconstitution of LAG-3 wild-type and cytoplasmic domain mutants in LAG-3−/− T cells, in vitro expansion assays European journal of immunology High 12672063
2005 LAG-3 negatively regulates T cell homeostasis; LAG-3-deficient mice accumulate twice as many T cells with age, and LAG-3−/− T cells show enhanced homeostatic expansion in lymphopenic hosts. Ectopic expression of wild-type LAG-3, but not a signaling-defective mutant, abrogates this deregulated expansion. Regulatory T cells depend on LAG-3 for optimal suppression of T cell homeostasis. LAG-3−/− mice, adoptive transfer into lymphopenic hosts, retroviral ectopic expression of wild-type vs. signaling-defective LAG-3, anti-LAG-3 mAb treatment in vivo Journal of immunology High 15634887
2004 LAG-3 negatively regulates T cell expansion in vivo: LAG-3−/− mice show delayed cell cycle arrest and increased T cell expansion after superantigen stimulation, increased memory T cells after viral infection, and enlarged memory T cell pools. LAG-3 controls the size of the memory T cell pool. LAG-3−/− mice, superantigen SEB stimulation in vivo, adoptive transfer of LAG-3−/− OT-II T cells, Sendai virus and murine gammaherpesvirus infection models Journal of immunology High 15100286
2002 LAG-3Ig (soluble LAG-3) binds MHC class II molecules in plasma membrane lipid rafts on immature human dendritic cells (DCs) and induces DC maturation: rapid morphological changes, upregulation of costimulatory molecules, IL-12 and TNF-alpha production, and enhanced capacity to stimulate naive T cells for Th1 responses. These effects were not observed with MHC class II-specific mAbs. LAG-3Ig fusion protein treatment of human monocyte-derived DCs, flow cytometry, cytokine ELISA, T cell co-culture assays, confocal microscopy Journal of immunology High 11937541
2003 LAG-3-induced MHC class II signaling in human DCs involves activation of PLCγ2, p72syk, PI3K/Akt, p42/44 ERK, and p38 MAPK pathways, all required for DC maturation. LAG-3 engagement versus anti-MHC class II antibody produces different phosphorylation patterns of c-Akt, indicating qualitative signaling differences dependent on the natural ligand. Phospho-protein analysis, kinase inhibitor studies, Western blotting in human monocyte-derived DCs, confocal microscopy with soluble LAG-3 Blood High 12775570
2017 LAG3 intrinsically limits regulatory T cell (Treg) proliferation and function at inflammatory sites. Treg-specific LAG3 deletion (using Foxp3-Cre) reduces autoimmune diabetes in NOD mice by enhancing Treg proliferation, IL-2-STAT5 signaling, and Eos expression in intra-islet Tregs. LAG3-deficient Tregs outcompete wild-type Tregs specifically at the inflammatory site. Treg-specific LAG3 conditional knockout (Foxp3-Cre x Lag3-flox), RNA sequencing of intra-islet vs. peripheral Tregs, cotransfer competition experiments, STAT5 phosphorylation assays Science immunology High 28783703
2024 LAG-3 sustains TOX expression in exhausted CD8 T cells during chronic infection and cancer, maintaining Tex cell durability. LAG-3 controls a CD94/NKG2+ subset of exhausted T cells with enhanced cytotoxicity via recognition of the stress ligand Qa-1b. PD-1 and LAG-3 have distinct non-redundant roles: PD-1 primarily regulates proliferation while LAG-3 primarily regulates effector functions of exhausted T cells. LAG-3 and PD-1 single/double knockout mice in chronic LCMV infection, flow cytometry, TOX expression analysis, cytotoxicity assays, NKG2/Qa-1b interaction studies Cell High 39121847
2024 Lag3 supports Foxp3+ regulatory T cell suppressive function by restraining Myc-dependent metabolic programming. Lag3 mutation in Tregs increases Myc expression to levels seen in Th1 effector cells, activates PI3K-Akt-Rictor signaling, and dysregulates glycolytic metabolism. Inhibiting PI3K, Rictor, or the Myc target enzyme Ldha restores normal metabolism and suppressive function in Lag3-mutant Tregs. Treg-specific Lag3 mutant mouse models, RNA sequencing, metabolic profiling, PI3K/Rictor/Ldha inhibitor rescue experiments, in vivo autoimmunity models Immunity High 39236718
2005 LAG-3 co-localizes with CD3, CD4 or CD8 in cholesterol-rich lipid raft aggregations during primary T cell activation. Blocking LAG-3/MHC class II interactions with anti-LAG-3 mAb augments CD69 expression, T cell expansion, cell cycle entry, and Th1 (but not Th2) cytokine production in both CD4+ and CD8+ primary human T cells at low antigen concentrations. Confocal microscopy for co-localization, anti-LAG-3 blocking mAb, BrdU incorporation, flow cytometry, cytokine ELISA in primary human T cells Immunology Medium 15885122
2015 CD4+CD25−LAG3+ regulatory T cells (LAG3+ Tregs) suppress humoral immune responses and B cell activity through TGF-β3 production in an Egr2- and Fas-dependent manner. This suppression requires PD-1 expression on B cells. In vitro co-culture suppression assays, TGF-β3 neutralization, Egr2-deficient mice, Fas-deficient cells, PD-1-deficient B cells, murine lupus model Nature communications Medium 25695838
2018 LAG-3 expressed on Foxp3+ regulatory T cells mediates contact-dependent suppression of CX3CR1+ intestinal macrophages via MHC class II engagement, inhibiting IL-23 and IL-1β production from macrophages and thereby restraining ILC3-mediated IL-22 production and colitis. Treg-macrophage co-culture contact-dependency assays, LAG-3 blocking antibodies, Treg-specific depletion, colitis mouse model with ILC3 transfer Immunity Medium 30097293
2005 Soluble LAG-3 (sLAG-3), but not an MHC class II-specific mAb, reduces differentiation of monocytes into macrophages (in GM-CSF) and into dendritic cells (in GM-CSF + IL-4), as shown by decreased CD14 and CD1a expression. DCs differentiated in the presence of sLAG-3 have impaired antigen-presentation capacity. sLAG-3 treatment of human monocytes, flow cytometry for differentiation markers, T cell proliferation assays Immunology Medium 15720438
2003 Soluble LAG-3Ig engagement of MHC class II on immature human DCs induces a distinct chemokine profile: production of IL-8 and MIP-1α/CCL3 (inflammatory), and MDC/CCL22 and TARC/CCL17 (lymph node-homing), with CCR5 downregulation and CCR7 upregulation on DC surface, potentially directing DC migration to lymph nodes. LAG-3Ig treatment of human monocyte-derived DCs, cytokine ELISA, flow cytometry for chemokine receptors, chemotaxis assays Vaccine Medium 12547595
2024 Amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 and facilitates binding, internalization, transmission, and toxicity of pathologic α-synuclein preformed fibrils (PFF). Deletion of both Aplp1 and Lag3 eliminates dopaminergic neuron loss and behavioral deficits induced by α-syn PFF. Anti-Lag3 prevents α-syn PFF internalization by disrupting the Aplp1-Lag3 interaction. Co-immunoprecipitation of Aplp1-Lag3, double KO mice (Aplp1 and Lag3), α-synuclein PFF injection model, anti-Lag3 antibody blockade, behavioral tests, dopaminergic neuron counts Nature communications Medium 38821932
2021 LAG3 is not expressed by neurons in human or murine brains. Overexpression of LAG3 in human neural cells did not worsen α-synuclein pathology ex vivo. LAG3 knockout did not affect survival of A53T α-synuclein transgenic mice or seeded α-synuclein lesions in hippocampal slice cultures, though LAG3 does interact with α-synuclein fibrils with limited specificity. Immunohistochemistry, RNA-seq, Western blot, LAG3 overexpression in neural cells, LAG3 KO mice, hippocampal slice culture seeding assay, survival analysis EMBO molecular medicine Medium 34309222
2023 LAG-3 expression in microglia is induced by IFN-γ via the STAT1 pathway. Both membrane and soluble forms of LAG-3 are upregulated in IFN-γ-activated microglia. Soluble LAG-3 production is regulated by metalloproteinases ADAM10 and ADAM17. LAG-3 knockdown in microglia promotes nitric oxide production by IFN-γ, indicating LAG-3 restrains microglial activation. siRNA knockdown of STAT1, metalloproteinase inhibitors (ADAM10/17), IFN-γ stimulation of BV2 and primary microglia, in vivo intracisterna magna IFN-γ injection, nitric oxide assay Frontiers in cellular neuroscience Medium 38026700
2018 A natural subset of plasma cells distinctively expressing LAG-3 (along with CD200, PD-L1, and PD-L2) produces IL-10 and mediates immune suppression in vivo. These LAG-3+ regulatory plasma cells develop from B cell subsets in a BCR-dependent manner and upregulate IL-10 via a TLR-driven mechanism upon challenge. Flow cytometry identification of LAG-3+ plasma cell subset, BCR-dependent development assays, TLR stimulation, IL-10 ELISA, in vivo challenge models, transcriptomic and epigenomic profiling Immunity Medium 30005826

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 1722 27192565
2017 LAG3 (CD223) as a cancer immunotherapy target. Immunological reviews 755 28258692
2018 Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell 712 30580966
2015 Clinical blockade of PD1 and LAG3--potential mechanisms of action. Nature reviews. Immunology 510 25534622
2020 LAG-3: from molecular functions to clinical applications. Journal for immunotherapy of cancer 360 32929051
2023 Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy. Journal of hematology & oncology 302 37670328
2019 Lymphocyte-activation gene 3 (LAG3): The next immune checkpoint receptor. Seminars in immunology 297 31604537
2004 Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. Journal of immunology (Baltimore, Md. : 1950) 279 15100286
2023 LAG-3 as the third checkpoint inhibitor. Nature immunology 265 37488429
2011 LAG-3 in Cancer Immunotherapy. Current topics in microbiology and immunology 265 21086108
2005 Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). Journal of immunology (Baltimore, Md. : 1950) 262 15634887
2003 The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. European journal of immunology 248 12672063
2018 LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells. Immunity 212 30005826
2017 CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells. Frontiers of medicine 204 28625015
2024 LAG-3, TIM-3, and TIGIT: Distinct functions in immune regulation. Immunity 201 38354701
2002 Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). European journal of immunology 173 12209638
2018 LAG3+ Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis. Immunity 170 30097293
2022 Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity. Immunity 167 35413245
2022 LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nature immunology 167 35437325
2021 Understanding LAG-3 Signaling. International journal of molecular sciences 166 34067904
2005 The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunology 146 15885122
2002 Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223). Journal of immunology (Baltimore, Md. : 1950) 145 11937541
2017 LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes. Science immunology 139 28783703
2022 Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer. Frontiers in immunology 137 35111155
2022 The promising immune checkpoint LAG-3 in cancer immunotherapy: from basic research to clinical application. Frontiers in immunology 137 35958563
2021 LAG3's Enigmatic Mechanism of Action. Frontiers in immunology 136 33488626
2024 Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity. Cell 127 39121849
2017 Tim-3, Lag-3, and TIGIT. Current topics in microbiology and immunology 126 28900677
2003 LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination. Trends in immunology 121 14644131
2003 MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223). Blood 116 12775570
2015 TGF-β3-expressing CD4+CD25(-)LAG3+ regulatory T cells control humoral immune responses. Nature communications 110 25695838
2004 Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223). Journal of immunology (Baltimore, Md. : 1950) 107 15557174
2011 The CD4-like molecule LAG-3, biology and therapeutic applications. Expert opinion on therapeutic targets 105 21142803
2022 Molecular Pathways and Mechanisms of LAG3 in Cancer Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 103 35579997
2024 Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses. Nature medicine 102 38504015
2022 Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer. Nature cancer 94 36585453
2019 New emerging targets in cancer immunotherapy: the role of LAG3. ESMO open 90 31231559
2024 LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity. Cell 86 39121847
2019 PD-1 and LAG-3 Dominate Checkpoint Receptor-Mediated T-cell Inhibition in Renal Cell Carcinoma. Cancer immunology research 86 31484656
2022 LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors. International journal of molecular sciences 74 36077354
2014 LAG3 expression in active Mycobacterium tuberculosis infections. The American journal of pathology 68 25549835
2021 LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies. EMBO molecular medicine 65 34309222
2022 LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition. Nature immunology 64 35761082
2024 Immune-checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart. Nature reviews. Cancer 63 38982146
2020 Recalling the Biological Significance of Immune Checkpoints on NK Cells: A Chance to Overcome LAG3, PD1, and CTLA4 Inhibitory Pathways by Adoptive NK Cell Transfer? Frontiers in immunology 61 31998304
2012 Roles of LAG3 and EGR2 in regulatory T cells. Annals of the rheumatic diseases 60 22460149
2024 Promising immunotherapy targets: TIM3, LAG3, and TIGIT joined the party. Molecular therapy. Oncology 59 38596295
2022 Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor. Cells 58 35954196
2021 Seven mysteries of LAG-3: a multi-faceted immune receptor of increasing complexity. Immunotherapy advances 55 35265944
2005 LAG-3 (CD223) reduces macrophage and dendritic cell differentiation from monocyte precursors. Immunology 55 15720438
2025 Ligand-induced ubiquitination unleashes LAG3 immune checkpoint function by hindering membrane sequestration of signaling motifs. Cell 50 40101708
2021 PD-1 and LAG-3 blockade improve anti-tumor vaccine efficacy. Oncoimmunology 48 33996265
2020 Progress of immune checkpoint LAG-3 in immunotherapy. Oncology letters 48 32963613
2024 The immune checkpoint receptor LAG3: Structure, function, and target for cancer immunotherapy. The Journal of biological chemistry 47 38556085
2021 Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation. Molecular psychiatry 46 34650207
2020 Molecular, clinicopathological, and immune correlates of LAG3 promoter DNA methylation in melanoma. EBioMedicine 41 32861198
2024 Relatlimab: a novel drug targeting immune checkpoint LAG-3 in melanoma therapy. Frontiers in pharmacology 40 38269271
2023 LAG-3 Inhibitors: Novel Immune Checkpoint Inhibitors Changing the Landscape of Immunotherapy. Biomedicines 40 37509517
2020 LAG3 (CD223) and autoimmunity: Emerging evidence. Journal of autoimmunity 40 32576412
2022 The Role of TIM-3 and LAG-3 in the Microenvironment and Immunotherapy of Ovarian Cancer. Biomedicines 39 36359346
2003 MHC class II engagement by its ligand LAG-3 (CD223) leads to a distinct pattern of chemokine and chemokine receptor expression by human dendritic cells. Vaccine 39 12547595
2024 Astragalus polysaccharide ameliorates CD8+ T cell dysfunction through STAT3/Gal-3/LAG3 pathway in inflammation-induced colorectal cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 38 38278025
2021 Gene of the month: lymphocyte-activation gene 3 (LAG-3). Journal of clinical pathology 38 34183437
2021 LAG3 and Its Ligands Show Increased Expression in High-Risk Uveal Melanoma. Cancers 36 34503258
2024 Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein. Nature communications 35 38821932
2024 Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 35 38900987
2021 Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples. Frontiers in immunology 33 34267742
2022 LAG3 blockade coordinates with microwave ablation to promote CD8+ T cell-mediated anti-tumor immunity. Journal of translational medicine 32 36180876
2021 High HDL-Cholesterol Paradox: SCARB1-LAG3-HDL Axis. Current atherosclerosis reports 32 33398433
2024 Analysis of PD1, LAG3, TIGIT, and TIM3 expression in human lung adenocarcinoma reveals a 25-gene signature predicting immunotherapy response. Cell reports. Medicine 30 39591972
2018 Early Growth Response Gene 2-Expressing CD4+LAG3+ Regulatory T Cells: The Therapeutic Potential for Treating Autoimmune Diseases. Frontiers in immunology 30 29535721
2024 Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming. Immunity 29 39236718
2022 LAG3 Regulates T Cell Activation and Plaque Infiltration in Atherosclerotic Mice. JACC. CardioOncology 29 36636446
2020 Lymphocyte-Activation Gene 3 (LAG3) Protein as a Possible Therapeutic Target for Parkinson's Disease: Molecular Mechanisms Connecting Neuroinflammation to α-Synuclein Spreading Pathology. Biology 29 32340360
2020 Genomic and immunologic correlates of LAG-3 expression in cancer. Oncoimmunology 29 32923111
2019 Roles, function and relevance of LAG3 in HIV infection. PLoS pathogens 29 30653605
2024 LAG-3 : recent developments in combinational therapies in cancer. Cancer science 28 38702996
2022 Fewer LAG-3+ T Cells in Relapsing-Remitting Multiple Sclerosis and Type 1 Diabetes. Journal of immunology (Baltimore, Md. : 1950) 28 35022272
2023 Lag-3 expression and clinical outcomes in metastatic melanoma patients treated with combination anti-lag-3 + anti-PD-1-based immunotherapies. Oncoimmunology 27 37808404
2021 Triple-Negative Breast Cancer: Intact Mismatch Repair and Partial Co-Expression of PD-L1 and LAG-3. Frontiers in immunology 27 33717059
2023 LAG-3 transcriptomic expression patterns across malignancies: Implications for precision immunotherapeutics. Cancer medicine 26 37132280
2018 Lymphocyte activation gene 3 (Lag3) expression is increased in prion infections but does not modify disease progression. Scientific reports 26 30279468
2022 LAG3-PD-1 Combo Overcome the Disadvantage of Drug Resistance. Frontiers in oncology 23 35494015
2025 Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity. Cell 22 40592325
2024 Advances in LAG3 cancer immunotherapeutics. Trends in cancer 22 39603977
2017 Function and regulation of LAG3 on CD4+CD25- T cells in non-small cell lung cancer. Experimental cell research 22 28935468
2024 TIM-3, LAG-3, or 2B4 gene disruptions increase the anti-tumor response of engineered T cells. Frontiers in immunology 20 38510235
2022 Deciphering molecular and cellular ex vivo responses to bispecific antibodies PD1-TIM3 and PD1-LAG3 in human tumors. Journal for immunotherapy of cancer 19 36319064
2024 Clinical response and pathway-specific correlates following TIGIT-LAG3 blockade in myeloma: the MyCheckpoint randomized clinical trial. Nature cancer 18 39187595
2019 PD-L1, LAG3, and HLA-DR are increasingly expressed during smoldering myeloma progression. Annals of hematology 18 31053880
2021 Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma. Cancers 17 34072549
2020 PD-L1 and LAG-3 expression in advanced cutaneous squamous cell carcinomas. Journal of cutaneous pathology 17 32279340
2017 Expression of TIM-3 and LAG-3 in extranodal NK/T cell lymphoma, nasal type. Histology and histopathology 17 28901003
2024 Cutting Edge: LAG3 Dimerization Is Required for TCR/CD3 Interaction and Inhibition of Antitumor Immunity. Journal of immunology (Baltimore, Md. : 1950) 16 38775415
2024 Loss of tumor suppressors promotes inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression. Nature communications 16 38997291
2023 LAG-3 expression in microglia regulated by IFN-γ/STAT1 pathway and metalloproteases. Frontiers in cellular neuroscience 15 38026700
2020 Ectopic expression of LAG-3 in non-small-cell lung cancer cells and its clinical significance. Journal of clinical laboratory analysis 15 32077528
2023 LAG-3 expression in tumor microenvironment of triple-negative breast cancer. Turkish journal of medical sciences 14 36945923
2019 LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target. Journal of immunotherapy (Hagerstown, Md. : 1997) 14 31219974
2023 LAG3 in gastric cancer: it's complicated. Journal of cancer research and clinical oncology 13 37311986

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