Affinage

HAVCR2

Hepatitis A virus cellular receptor 2 · UniProt Q8TDQ0

Length
301 aa
Mass
33.4 kDa
Annotated
2026-06-10
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HAVCR2 (TIM-3) is a type I transmembrane immune receptor that exerts context-dependent co-stimulatory and co-inhibitory control across immune and non-immune cell types through multiple ligands and intracellular adaptors (PMID:16286920, PMID:34435619, PMID:31848194). Several ligands engage its IgV domain: galectin-9 binding triggers calcium flux and selective death of TH1 cells (PMID:16286920) and suppresses NK cytotoxicity and proliferation (PMID:39773563); phosphatidylserine engagement drives TCR-proximal NF-κB signaling and IL-2 secretion in T cells (PMID:34435619) but on NK cells promotes TIM-3 phosphorylation that lets it compete with PI3K p110 for the p85 regulatory subunit, suppressing Akt/mTORC1 signaling and cytotoxicity (PMID:31848194); and HMGB1 binding inhibits NF-κB in CD4+ T cells during sepsis (PMID:34933101). On dendritic cells TIM-3 restrains anti-tumor immunity by preventing ROS-driven NLRP3 inflammasome activation and IL-1β/IL-18 production (PMID:34108686), and mediates phosphatidylserine-dependent trogocytosis of CD8+ T cells (PMID:35316223); its cytoplasmic-tail adaptor Bat3 limits DC steroidogenesis and the unfolded protein response to preserve effector T cell responses (PMID:35275752). In microglia, TGFβ-induced TIM-3 interacts with SMAD2 and TGFBR2 through its C-terminal tail to enhance SMAD2 phosphorylation and maintain homeostasis, restraining a neurodegenerative phenotype (PMID:40205047). Surface abundance is set post-translationally: DHHC9-mediated palmitoylation at Cys296 blocks HRD1-dependent ubiquitination and degradation, stabilizing the receptor and promoting exhaustion (PMID:39546589). Germline missense mutations (p.Tyr82Cys, p.Ile97Met) that misfold the protein and abolish surface expression cause hemophagocytic lymphohistiocytosis and subcutaneous panniculitis-like T-cell lymphoma through persistent immune activation and TNF-α/IL-1β hypersecretion (PMID:30374066).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2005 High

    Establishing the first functional ligand answered how TIM-3 transmits a regulatory signal, defining galectin-9 as a ligand that eliminates TH1 cells and suppresses autoimmunity.

    Evidence Calcium flux, cell aggregation/death assays in Tim-3+ T cells and in vivo galectin-9 administration in mouse autoimmunity

    PMID:16286920

    Open questions at the time
    • Did not resolve the binding interface or downstream signaling biochemistry
    • Human-system relevance later contested
  2. 2013 Medium

    A negative report challenged the galectin-9 model by failing to detect specific binding to human or murine TIM-3, raising the question of which ligand drives human T cell function.

    Evidence Binding studies and T cell activation assays in human and murine systems plus HIV patient T cell assays

    PMID:23555261

    Open questions at the time
    • Negative binding result does not exclude low-affinity or context-dependent interaction
    • Single-lab discrepancy with prior in vivo data
  3. 2015 High

    Identifying a co-stimulatory role in mast cells showed TIM-3 is not exclusively inhibitory, augmenting FcεRI-proximal Lyn-dependent signaling.

    Evidence Gain- and loss-of-function in mast cells with Lyn pathway, degranulation and cytokine readouts

    PMID:26598760

    Open questions at the time
    • Direct ligand driving mast cell signaling not defined
    • Cytoplasmic motifs mediating Lyn engagement not mapped
  4. 2018 High

    Germline loss-of-function mutations established TIM-3 as a causal restraint on inflammation in humans, linking surface loss to hyperinflammatory disease.

    Evidence Sequencing, surface-expression analysis and cytokine quantification in HLH/SPTCL patients with cell models

    PMID:30374066

    Open questions at the time
    • Cell type responsible for the inflammatory phenotype not pinpointed
    • Mechanism connecting misfolding to cytokine hypersecretion not fully defined
  5. 2019 High

    Defining the NK-cell mechanism showed how PS engagement converts TIM-3 into an inhibitor of metabolic-cytotoxic signaling by competing for PI3K p85.

    Evidence Phosphorylation and competitive p85-binding assays, Akt/mTORC1 analysis, NK functional assays and in vivo HCC model

    PMID:31848194

    Open questions at the time
    • Phosphorylation residues mediating p85 competition not enumerated
    • Generality beyond NK cells unresolved
  6. 2021 High

    Reconciling co-stimulatory vs co-inhibitory roles, PS-binding-site mutagenesis showed PS engagement in T cells promotes NF-κB/IL-2 and alters CD28 phosphorylation, defining a context-dependent acute signal.

    Evidence PS-binding-site mutagenesis, NF-κB reporter, IL-2 ELISA, CD28 phosphorylation and antibody blockade in Jurkat cells

    PMID:34435619

    Open questions at the time
    • How the same PS ligand yields opposite outcomes across cell types not mechanistically unified
    • Endogenous T cell validation beyond Jurkat needed
  7. 2021 High

    Cell-type-specific knockouts revealed the dominant anti-tumor checkpoint function resides in dendritic cells, where TIM-3 suppresses the NLRP3 inflammasome.

    Evidence Conditional DC/CD4/CD8 KO with genetic epistasis, scRNA-seq, ROS and inflammasome assays, IL-1β/IL-18 blockade and tumor models

    PMID:34108686

    Open questions at the time
    • Molecular link from TIM-3 to ROS/NLRP3 suppression not biochemically defined
    • Ligand driving DC-intrinsic signal not identified
  8. 2021 High

    TIM-3 was shown to act intracellularly in macrophages, targeting the viral sensor NF90 for TRIM47-mediated K48 ubiquitination to suppress antiviral innate immunity.

    Evidence Co-IP, K48 ubiquitination and domain-mapping assays, Tim-3 inactivation, stress-granule and eIF2α/PKR readouts and in vivo VSV challenge

    PMID:34110282

    Open questions at the time
    • How a surface receptor accesses cytoplasmic NF90 not resolved
    • Relationship to canonical ligand-driven signaling unclear
  9. 2021 Medium

    HMGB1 was identified as a TIM-3 ligand inhibiting NF-κB in CD4+ T cells, contributing to sepsis-induced immunosuppression.

    Evidence Colocalization of HMGB1 and TIM-3, NF-κB analysis, conditional Tim-3 deletion and sepsis mortality model

    PMID:34933101

    Open questions at the time
    • Interaction based on colocalization rather than direct biochemical binding
    • Binding interface unmapped
  10. 2022 High

    The Bat3 adaptor was defined as an endogenous regulator of the TIM-3 tail, controlling DC steroidogenesis and the UPR to shape T cell quality.

    Evidence Bat3 conditional DC deletion, EAE and MC38-OVA models, steroidogenesis and acetyl-CoA assays, T cell phenotyping

    PMID:35275752

    Open questions at the time
    • Direct structural basis of Bat3 tail binding not detailed
    • Whether ligand engagement modulates Bat3 release unknown
  11. 2022 High

    A trogocytosis mechanism explained how DC-intrinsic TIM-3 produces fratricide of tumor-reactive CD8+ T cells via PS-dependent membrane transfer.

    Evidence Human melanoma TIL analysis, PS-blocking, DC-specific conditional KO and two melanoma models with trogocytosis/fratricide assays

    PMID:35316223

    Open questions at the time
    • Molecular machinery executing membrane transfer downstream of TIM-3 not defined
  12. 2022 Medium

    Tumor-cell-intrinsic TIM-3 roles were defined: in glioblastoma it drives NF-κB/IL-6 to polarize macrophages, and in melanoma it restrains pro-proliferative MAPK signaling.

    Evidence Gain/loss-of-function in glioma and melanoma cells, NF-κB/IL-6 and MAPK pathway analyses, macrophage co-culture and in vivo pharmacologic rescue

    PMID:35980306 PMID:36325060

    Open questions at the time
    • Cancer-cell-intrinsic ligands and proximal signaling steps undefined
    • Single-lab findings per tumor type
  13. 2024 High

    Post-translational control of receptor abundance was established: DHHC9-mediated Cys296 palmitoylation blocks HRD1 binding and degradation, a node exploitable to reduce exhaustion.

    Evidence Palmitoylation and Cys296 mutagenesis, Co-IP with HRD1, ubiquitination assays, DHHC9 knockdown, CAR-T exhaustion and peptidic inhibitor experiments

    PMID:39546589

    Open questions at the time
    • Whether palmitoylation status is signal-regulated in vivo unclear
    • Stoichiometry with HRD1 vs other ligases not resolved
  14. 2024 Medium

    Comparative ligand testing on NK cells re-affirmed galectin-9 as the most consistent suppressive ligand while revealing TIM-3-independent CD44 signaling.

    Evidence NK killing, proliferation and cytokine assays with four ligands, TIM-3-blocking antibodies and HNSCC patient NK cells

    PMID:39773563

    Open questions at the time
    • Relative ligand affinities and binding sites not biochemically ranked
    • Single-lab functional comparison
  15. 2025 High

    A non-immune homeostatic role was defined: TGFβ-induced microglial TIM-3 binds SMAD2/TGFBR2 to amplify SMAD2 phosphorylation, restraining a neurodegenerative microglial phenotype.

    Evidence Co-IP (TIM-3 with SMAD2 and TGFBR2), SMAD2 phosphorylation assays, microglia-specific Havcr2 KO, 5xFAD model and sc/snRNA-seq

    PMID:40205047

    Open questions at the time
    • Structural basis of TIM-3 tail engagement with SMAD2/TGFBR2 not resolved
    • Whether ligand binding gates this interaction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying biochemical model for how a single cytoplasmic tail toggles between activating (NF-κB/IL-2), inhibitory (PI3K competition), degradative (NF90/TRIM47), and adaptor/scaffold (Bat3, SMAD2/TGFBR2) functions across cell types remains unresolved.
  • No structure of the signaling-competent tail with its partners
  • Ligand-specific signaling outputs not mechanistically separated
  • Conflicting galectin-9 binding data across human/murine systems unreconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
BAG6LGALS9PIK3R1SMAD2SYVN1TGFBR2ZBTB32ZDHHC9

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Galectin-9 was identified as a functional ligand for TIM-3. Galectin-9 binding to TIM-3 induced intracellular calcium flux, cell aggregation, and selective death of TH1 cells in vitro; in vivo administration caused loss of IFN-γ-producing cells and suppression of TH1 autoimmunity in a TIM-3-dependent manner. In vitro calcium flux assay, cell aggregation/death assays with Tim-3-expressing T cells, in vivo galectin-9 administration in mouse autoimmunity model Nature immunology High 16286920
2013 NEGATIVE FINDING: Extensive binding studies did not yield evidence for specific interaction between galectin-9 and human or murine TIM-3, and galectin-9 did not affect activation of human T cells. Anti-TIM-3 antibodies failed to increase anti-HIV T cell responses in vitro. T cell activation assays, extensive binding studies (human and murine TIM-3 vs. galectin-9), HIV patient T cell functional assays PLoS pathogens Medium 23555261
2015 TIM-3 enhances FcεRI-proximal signaling in mast cells by acting at a receptor-proximal point to augment Lyn kinase-dependent pathways, thereby modulating both immediate-phase degranulation and late-phase cytokine production downstream of FcεRI ligation. Gain- and loss-of-function approaches in mast cells, signaling pathway analysis (Lyn kinase), degranulation and cytokine production assays The Journal of experimental medicine High 26598760
2018 Germline missense mutations in HAVCR2 (p.Tyr82Cys and p.Ile97Met) cause protein misfolding and abolish TIM-3 plasma membrane expression, leading to persistent immune activation and increased production of TNF-α and IL-1β, promoting hemophagocytic lymphohistiocytosis (HLH) and subcutaneous panniculitis-like T cell lymphoma (SPTCL). Genetic sequencing, protein expression analysis (Western blot/surface expression), cytokine quantification in patient samples and cell models Nature genetics High 30374066
2019 Phosphatidylserine (PtdSer) engagement promotes phosphorylation of TIM-3 on NK cells, which then competes with PI3K p110 subunit to bind the p85 regulatory subunit, thereby inhibiting downstream Akt/mTORC1 signaling and suppressing NK cell cytokine secretion and cytotoxic activity in hepatocellular carcinoma. Phosphorylation assays, competitive binding of TIM-3 vs. PI3K p110 for p85, Akt/mTORC1 pathway analysis, NK cell functional assays, in vivo HCC tumor model with TIM-3 blockade Cancer research High 31848194
2021 TIM-3 on dendritic cells (DCs) restrains anti-tumor immunity by preventing NLRP3 inflammasome activation; loss of TIM-3 in DCs leads to increased reactive oxygen species accumulation, NLRP3 inflammasome activation, and IL-1β/IL-18-dependent promotion of CD8+ effector and stem-like T cells. TIM-3 deletion in DCs—but not in CD4+ or CD8+ T cells—was responsible for the anti-tumor effect. Conditional knockout of TIM-3 in DCs, CD4+ T cells, and CD8+ T cells (cell-type-specific genetic epistasis); single-cell RNA sequencing; ROS measurement; inflammasome activity assays; IL-1β/IL-18 blockade experiments; tumor growth assays Nature High 34108686
2021 TIM-3 binding to phosphatidylserine (PS) promotes NF-κB signaling and IL-2 secretion downstream of TCR stimulation in Jurkat T cells; this co-stimulatory activity is blocked by mutating the PS-binding site or by occluding it with antibody. TIM-3 signaling also alters CD28 phosphorylation. PS-binding site mutagenesis, NF-κB reporter assays, IL-2 ELISA, CD28 phosphorylation analysis, antibody blockade of PS-binding site in Jurkat cells The Biochemical journal High 34435619
2021 TIM-3 promotes ubiquitination and proteasomal degradation of NF90 (a virus sensor) in macrophages during VSV infection by recruiting E3 ubiquitin ligase TRIM47 to the zinc finger domain of NF90, initiating K48-linked ubiquitination at Lys297, thereby suppressing stress granule formation and antiviral innate immunity. Co-immunoprecipitation, ubiquitination assays (K48-linkage), domain mapping, Tim-3 conditional inactivation, downstream stress granule marker analysis (G3BP1, TIA-1), eIF2α/PKR phosphorylation assays, in vivo VSV challenge eLife High 34110282
2022 TIM-3 on dendritic cells (APCs) mediates trogocytosis—transfer of membrane fragments from APCs to T cells. TIM-3 blockade on Tim-3+ APCs disrupted phosphatidylserine-dependent trogocytosis of activated CD8+ T cells and PD-1+Tim-3+ TILs. Trogocytosed CD8+ T cells presented tumor peptide-MHC complexes and became targets of fratricide killing, which was reversed by TIM-3 blockade. Conditional deletion of TIM-3 in DCs but not CD8+ T cells impeded trogocytosis in vivo. Human melanoma TIL analysis, PS-blocking experiments, DC-specific TIM-3 conditional deletion in vivo, two melanoma mouse models, functional assays for trogocytosis and fratricide T cell killing The Journal of clinical investigation High 35316223
2022 Bat3, an adaptor protein that binds the cytoplasmic tail of TIM-3, acts as an endogenous regulator of DC function. Loss of Bat3 in DCs leads to hyperactive unfolded protein response and redirects acetyl-CoA toward increased cell-intrinsic steroidogenesis, which suppresses T cell responses in a paracrine manner; this skews the immune response toward regulatory T cells and exhausted CD8+ TILs. Bat3 conditional deletion in DCs, autoimmunity (EAE) and cancer (MC38-OVA) mouse models, steroidogenesis assays, acetyl-CoA metabolic analysis, T cell compartment phenotyping Science immunology High 35275752
2024 TIM-3 is palmitoylated by the palmitoyltransferase DHHC9 at cysteine 296 (Cys296). Palmitoylation stabilizes TIM-3 by preventing its binding to E3 ubiquitin ligase HRD1, thereby suppressing TIM-3 polyubiquitination and degradation. DHHC9 knockdown attenuated CAR-T cell exhaustion, and a peptidic inhibitor of TIM-3 palmitoylation accelerated TIM-3 degradation and enhanced antitumor immunity. Palmitoylation assays, site-directed mutagenesis (Cys296), Co-IP with HRD1, ubiquitination assays, DHHC9 knockdown, CAR-T cell exhaustion assays, peptidic inhibitor experiments Science immunology High 39546589
2025 TGFβ signaling induces TIM-3 expression in microglia. TIM-3 in turn interacts with SMAD2 and TGFBR2 through its C-terminal tail, enhancing TGFβ signaling by promoting TGFBR-mediated SMAD2 phosphorylation; this maintains microglial homeostasis. Microglial-specific deletion of Havcr2 increases phagocytic activity and shifts microglia toward a neurodegenerative (MGnD/DAM) phenotype, ameliorating amyloid-β pathology and cognitive impairment in 5×FAD mice. Co-immunoprecipitation (TIM-3 with SMAD2 and TGFBR2), SMAD2 phosphorylation assays, microglia-specific conditional Havcr2 knockout (Cre-lox), 5×FAD Alzheimer's model behavioral and pathology analyses, single-nucleus and single-cell RNA sequencing Nature High 40205047
2021 In CD4+ T cells during sepsis, HMGB1 binds to TIM-3 and this interaction inhibits the NF-κB signaling pathway in TIM-3+ CD4+ T cells, contributing to sepsis-induced immunosuppression. Conditional or systemic deletion of Tim-3 reduced sepsis mortality. Colocalization analysis of HMGB1 and TIM-3 on CD4+ T cells, NF-κB signaling pathway analysis, conditional Tim-3 deletion in CD4+ T cells, in vivo sepsis mouse model mortality assay Molecular therapy Medium 34933101
2019 Tim-3 signaling in Vγ9Vδ2 T cells reduces perforin and granzyme B expression through an ERK1/2-dependent pathway, thereby suppressing cytotoxic killing of colon cancer cells. Tim-3 signaling activation experiments, perforin/granzyme B expression analysis, ERK1/2 pathway inhibition, cytotoxicity assays against colon cancer cells Experimental cell research Medium 31726050
2022 In glioblastoma cells, TIM-3 regulates IL-6 expression through NF-κB activation; cell-intrinsic TIM-3/IL-6 signaling induces macrophage migration and M2/anti-inflammatory polarization. Blocking IL-6 receptor with tocilizumab suppressed these effects and repressed GBM tumorigenicity in vivo. TIM-3 overexpression/knockdown in glioma cells, NF-κB pathway analysis, IL-6 quantification, macrophage co-culture migration and polarization assays, in vivo GBM tumor model with tocilizumab treatment iScience Medium 36325060
2022 Tim-3 expressed in macrophages suppresses neutrophil necroptosis during colitis by inhibiting the TLR4/NF-κB pathway; macrophage-specific Tim-3 knockout increased ROS-driven neutrophil necroptosis and colitis severity. RIP1/RIP3 or ROS inhibition reversed the inflammation in Tim-3 KO mice. Macrophage-specific Tim-3 conditional knockout mice, DSS-induced colitis model, TLR4/NF-κB pathway analysis, RIP1/RIP3 and ROS pharmacologic inhibitors, neutrophil necroptosis assays Redox biology Medium 38330550
2022 Tim-3 suppresses MHC-II expression in macrophages via the STAT1/CIITA pathway, thereby inhibiting MHC-II-mediated autoantigen presentation and CD4+ T cell activation. Overexpression or blockade of Tim-3 signaling altered MHC-II expression and clinical outcomes in EAE mice. Tim-3 overexpression/blockade in EAE mouse model, STAT1/CIITA pathway analysis, MHC-II expression assays, CD4+ T cell activation assays Frontiers in immunology Medium 35095844
2021 Tim-3 suppresses Th17-mediated autoimmune hepatitis through the p38/MKP-1 pathway; blocking Tim-3 increased Th17 cell frequency and p38/MKP-1 and p-JNK activation, elevating IL-17A and liver damage. Anti-Tim-3 blockade in Con A-induced mouse AIH model, p38 inhibitor experiments, MKP-1 and IL-17A quantification, liver histology/enzyme assays FEBS open bio Low 33728805
2016 T-bet transcription factor, induced in monocyte/macrophages by HCV core protein via gC1qR interaction and the JNK signaling pathway, drives Tim-3 expression; silencing T-bet decreases Tim-3 expression, enhances IL-12 secretion and STAT1 phosphorylation in macrophages. T-bet knockdown, HCV core protein stimulation of primary macrophages and THP-1 cells, JNK inhibitor (SP600125), T-bet/Tim-3 correlation analysis, IL-12/STAT1 phosphorylation assays Immunology Medium 27809352
2020 NEGATIVE FINDING: TIM-3 and CEACAM1 do not interact in cis or in trans. Extensive binding studies found no evidence of direct TIM-3–CEACAM1 interaction, and CEACAM1-mediated inhibition did not involve TIM-3. However, cytoplasmic sequences derived from TIM-3 independently induced inhibitory signaling in a human T cell reporter system. T cell reporter assay platform, extensive binding studies (cis and trans configurations), T cell co-expression analysis, cytoplasmic domain signaling assays European journal of immunology Medium 32222966
2024 Among TIM-3 ligands tested on NK cells, galectin-9 most consistently suppresses NK cell-mediated cytotoxicity and proliferation through TIM-3 signaling, while also promoting IFN-γ release in a TIM-3-dependent manner. Galectin-9-mediated suppression of proliferation also occurred through CD44 signaling (independent of TIM-3). In vitro NK cell killing, proliferation, and cytokine production assays with four TIM-3 ligands (galectin-9, PtdSer, HMGB1, CEACAM1), TIM-3-blocking antibodies, HNSCC patient NK cell studies, flow cytometry Journal for immunotherapy of cancer Medium 39773563
2020 TIM-3 expression in Jurkat T cells is associated with decreased glucose uptake and consumption, reduced lactate release, and decreased Glut1 (but not Glut2/3/4) expression, indicating TIM-3 suppresses T cell glycolysis. TIM-3 overexpression and knockout in Jurkat T cells, glucose uptake/consumption assays, lactate release measurement, glucose transporter expression analysis BMC immunology Low 32819283
2022 Inhibition of melanoma cell-intrinsic TIM-3 promotes tumor growth via enhanced phosphorylation of MAPK signaling mediators (pro-proliferative). Melanoma-specific TIM-3 overexpression attenuated tumorigenesis in both immunocompetent and immunocompromised mice. Pharmacologic MAPK inhibition reversed TIM-3-antibody-mediated tumor growth promotion. Melanoma-specific TIM-3 knockdown and overexpression in vivo (immunocompetent and T-cell-deficient mice), MAPK phosphorylation assays, MEK inhibitor combination experiments Cancer research Medium 35980306

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
2005 The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nature immunology 1669 16286920
2017 Tim-3 and its role in regulating anti-tumor immunity. Immunological reviews 698 28258697
2021 Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nature communications 520 33547304
2020 Tim-3 finds its place in the cancer immunotherapy landscape. Journal for immunotherapy of cancer 337 32601081
2021 TIM-3 restrains anti-tumour immunity by regulating inflammasome activation. Nature 324 34108686
2023 Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy. Journal of hematology & oncology 302 37670328
2011 Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends in immunology 202 21697013
2024 LAG-3, TIM-3, and TIGIT: Distinct functions in immune regulation. Immunity 201 38354701
2017 TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action. International journal of molecular sciences 190 28300768
2018 TIM-3, a promising target for cancer immunotherapy. OncoTargets and therapy 187 30410357
2018 Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome. Nature genetics 177 30374066
2021 TIM-3: An update on immunotherapy. International immunopharmacology 173 34224993
2012 Tim-3, a negative regulator of anti-tumor immunity. Current opinion in immunology 169 22226204
2013 Tim-3: an activation marker and activation limiter of innate immune cells. Frontiers in immunology 167 24339828
2014 Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion. Journal of immunology (Baltimore, Md. : 1950) 141 25086175
2011 TIM-3 and its regulatory role in immune responses. Current topics in microbiology and immunology 132 20700701
2019 Tim-3: A co-receptor with diverse roles in T cell exhaustion and tolerance. Seminars in immunology 130 31604535
2019 Tim-3 Hampers Tumor Surveillance of Liver-Resident and Conventional NK Cells by Disrupting PI3K Signaling. Cancer research 128 31848194
2017 Tim-3, Lag-3, and TIGIT. Current topics in microbiology and immunology 126 28900677
2013 Tim-3 expression in cervical cancer promotes tumor metastasis. PloS one 124 23335978
2018 Tim-3 expression and its role in hepatocellular carcinoma. Journal of hematology & oncology 117 30309387
2017 Molecular and clinical characterization of TIM-3 in glioma through 1,024 samples. Oncoimmunology 112 28919992
2023 TIM-3 as a promising target for cancer immunotherapy in a wide range of tumors. Cancer immunology, immunotherapy : CII 105 37567938
2016 TIM-3 Regulates Distinct Functions in Macrophages. Frontiers in immunology 104 27379093
2015 Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation. The Journal of experimental medicine 103 26598760
2023 TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory. Cancer cell 96 37802053
2006 TIM-3 in autoimmunity. Current opinion in immunology 90 17011764
2018 Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice. Cellular & molecular immunology 87 29735977
2021 Tim-3 regulates sepsis-induced immunosuppression by inhibiting the NF-κB signaling pathway in CD4 T cells. Molecular therapy : the journal of the American Society of Gene Therapy 78 34933101
2021 TIM-3 pathway dysregulation and targeting in cancer. Expert review of anticancer therapy 77 33334180
2018 Immune regulation by Tim-3. F1000Research 76 29560265
2021 Targeting Tim-3 in Cancer With Resistance to PD-1/PD-L1 Blockade. Frontiers in oncology 75 34631560
2013 TIM-3 does not act as a receptor for galectin-9. PLoS pathogens 72 23555261
2015 Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer. Oncotarget 68 26008981
2014 Regulation of T cell responses by the receptor molecule Tim-3. Immunologic research 68 24825777
2024 Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity. Science immunology 66 39546589
2019 Tim-3 suppresses the killing effect of Vγ9Vδ2 T cells on colon cancer cells by reducing perforin and granzyme B expression. Experimental cell research 62 31726050
2008 TIM-1 and TIM-3 proteins in immune regulation. Cytokine 62 18706830
2022 New Checkpoint Inhibitors on the Road: Targeting TIM-3 in Solid Tumors. Current oncology reports 61 35218498
2019 Molecular and immune correlates of TIM-3 (HAVCR2) and galectin 9 (LGALS9) mRNA expression and DNA methylation in melanoma. Clinical epigenetics 59 31747929
2022 Tim-3 mediates T cell trogocytosis to limit antitumor immunity. The Journal of clinical investigation 58 35316223
2024 Beyond T cell exhaustion: TIM-3 regulation of myeloid cells. Science immunology 55 38457514
2021 TIM-3 in Leukemia; Immune Response and Beyond. Frontiers in oncology 53 34660319
2015 Tim-3 expression represents dysfunctional tumor infiltrating T cells in renal cell carcinoma. World journal of urology 53 26253654
2018 TIM-3 expression in breast cancer. Oncoimmunology 51 30377566
2015 Tim-3 and Tim-4 as the potential targets for antitumor therapy. Human vaccines & immunotherapeutics 49 26211834
2016 Tim-3 is upregulated in human colorectal carcinoma and associated with tumor progression. Molecular medicine reports 48 28035413
2019 NK cell expression of Tim-3: First impressions matter. Immunobiology 47 30876792
2025 Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease. Nature 46 40205047
2022 Tim-3 adapter protein Bat3 acts as an endogenous regulator of tolerogenic dendritic cell function. Science immunology 46 35275752
2020 The Role of TIM-3 in Hepatocellular Carcinoma: A Promising Target for Immunotherapy? Frontiers in oncology 45 33425759
2022 Cancer cell intrinsic TIM-3 induces glioblastoma progression. iScience 43 36325060
2021 Phosphatidylserine binding directly regulates TIM-3 function. The Biochemical journal 43 34435619
2016 Tim-3: Expression on immune cells and roles at the maternal-fetal interface. Journal of reproductive immunology 42 27792886
2024 TIM-3+ CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies. Science immunology 41 38640253
2015 Identification of TIM-3 as a Leukemic Stem Cell Surface Molecule in Primary Acute Myeloid Leukemia. Oncology 40 26551150
2022 The Role of TIM-3 and LAG-3 in the Microenvironment and Immunotherapy of Ovarian Cancer. Biomedicines 39 36359346
2021 One Stone, Two Birds: The Roles of Tim-3 in Acute Myeloid Leukemia. Frontiers in immunology 39 33868234
2016 Role of Tim-3 in hepatitis B virus infection: An overview. World journal of gastroenterology 37 26900291
2025 TIM-3 teams up with PD-1 in cancer immunotherapy: mechanisms and perspectives. Molecular biomedicine 35 40332725
2024 Macrophage Tim-3 maintains intestinal homeostasis in DSS-induced colitis by suppressing neutrophil necroptosis. Redox biology 34 38330550
2022 Tim-3 Blockade Elicits Potent Anti-Multiple Myeloma Immunity of Natural Killer Cells. Frontiers in oncology 33 35280800
2020 Glial TIM-3 Modulates Immune Responses in the Brain Tumor Microenvironment. Cancer research 33 32094297
2021 TIM-3 in normal and malignant hematopoiesis: Structure, function, and signaling pathways. Cancer science 32 34159709
2010 TIM-3 as a new therapeutic target in systemic lupus erythematosus. Molecular biology reports 31 19768575
2022 Photophosphatidylserine Guides Natural Killer Cell Photoimmunotherapy via Tim-3. Journal of the American Chemical Society 29 35226805
2020 Association of TIM-3 expression with glucose metabolism in Jurkat T cells. BMC immunology 28 32819283
2007 TIM-3 as a therapeutic target in human inflammatory diseases. Expert opinion on therapeutic targets 28 17665973
2022 Tim-3 Expression Causes NK Cell Dysfunction in Type 2 Diabetes Patients. Frontiers in immunology 27 35464400
2020 TIM-3 and CEACAM1 do not interact in cis and in trans. European journal of immunology 27 32222966
2023 Soluble TIM-3 as a biomarker of progression and therapeutic response in cancers and other of human diseases. Biochemical pharmacology 26 36739094
2020 TIM-3: An emerging target in the liver diseases. Scandinavian journal of immunology 26 31486085
2022 Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II. Frontiers in immunology 25 35095844
2024 The role of Tim-3 blockade in the tumor immune microenvironment beyond T cells. Pharmacological research 24 39396768
2021 Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity. eLife 23 34110282
2020 ImmunoPET Imaging of TIM-3 in Murine Melanoma Models. Advanced therapeutics 23 33889713
2025 Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception. Cancer cell 22 40345189
2023 TIM-3 Expression and M2 Polarization of Macrophages in the TGFβ-Activated Tumor Microenvironment in Colorectal Cancer. Cancers 22 37894310
2017 Combined blockade of Tim-3 and MEK inhibitor enhances the efficacy against melanoma. Biochemical and biophysical research communications 21 28132803
2017 On the significance of Tim-3 expression in pancreatic cancer. Saudi journal of biological sciences 21 29551917
2015 Tim-3 pathway affects NK cell impairment in patients with active tuberculosis. Cytokine 21 26050547
2023 T-cell immunoglobulin and mucin-domain containing-3 (TIM-3): Solving a key puzzle in autoimmune diseases. International immunopharmacology 20 37290326
2022 Increased Expression of Tim-3 Is Associated With Depletion of NKT Cells In SARS-CoV-2 Infection. Frontiers in immunology 20 35250975
2022 Inhibition of Melanoma Cell-Intrinsic Tim-3 Stimulates MAPK-Dependent Tumorigenesis. Cancer research 19 35980306
2020 Differential expression of TIM-3 in circulation and tumor microenvironment of colorectal cancer patients. Clinical immunology (Orlando, Fla.) 19 32320745
2018 Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells. Journal of visualized experiments : JoVE 19 29553498
2018 Expression of Tim-3 in breast cancer tissue promotes tumor progression. International journal of clinical and experimental pathology 19 31938210
2006 Tim-3 expression in human kidney allografts. Transplant immunology 19 17331850
2024 Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice. The Journal of clinical investigation 18 38916965
2017 Role of TIM-3 in ovarian cancer. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 18 28357631
2017 High Tim-3 expression on AML blasts could enhance chemotherapy sensitivity. Oncotarget 18 29254227
2021 Tim-3 suppresses autoimmune hepatitis via the p38/MKP-1 pathway in Th17 cells. FEBS open bio 17 33728805
2020 TIM-3 and TIGIT are possible immune checkpoint targets in patients with bladder cancer. Urologic oncology 17 32665122
2020 Tim-3 Expression and MGMT Methylation Status Association With Survival in Glioblastoma. Frontiers in pharmacology 17 33041828
2020 Targeting TIM-3 in solid tumors: innovations in the preclinical and translational realm and therapeutic potential. Expert opinion on therapeutic targets 17 33103506
2018 Tim-3 blockade promotes iNKT cell function to inhibit HBV replication. Journal of cellular and molecular medicine 17 29602251
2023 T Cell Immunoglobulin and Mucin Domain 3 (TIM-3) in Cutaneous Melanoma: A Narrative Review. Cancers 16 36980583
2016 T-bet-mediated Tim-3 expression dampens monocyte function during chronic hepatitis C virus infection. Immunology 16 27809352
2025 Differential impact of TIM-3 ligands on NK cell function. Journal for immunotherapy of cancer 15 39773563

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