Affinage

TIMD4

T-cell immunoglobulin and mucin domain-containing protein 4 · UniProt Q96H15

Length
378 aa
Mass
41.6 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMD4 (TIM4) is a type I transmembrane phosphatidylserine (PS) recognition receptor on resident macrophages and dendritic cells that tethers apoptotic cells to phagocytes and orchestrates their clearance (efferocytosis) (PMID:17960135, PMID:18082433, PMID:20421466). PS binding occurs through a single Ca2+-coordinated pocket in the IgV domain supplemented by weaker ionic sites that make TIM4 sensitive to PS surface density, allowing it to discriminate high-PS apoptotic cells from intermediate-PS activated T cells (PMID:18082433, PMID:24706780). TIM4 functions as a tether rather than a signaling receptor: its cytoplasmic tail is dispensable and can be replaced by a GPI anchor without loss of engulfment, and uptake instead requires partner receptors and an intact cytoskeleton (PMID:19217291). Productive internalization depends on cooperation with the TAM-family receptor MERTK, which docks onto TIM4 via a direct IgV–fibronectin type-III domain contact in a two-step mechanism—TIM4-dependent capture followed by MERTK-driven phosphorylation and engulfment through MEK/ERK, AKT, FAK, and STAT6 (PMID:24515440, PMID:30846565, PMID:32640697), and TIM4 also recruits β1 integrins to activate Src-family kinases, FAK, PI3K, and Rho-GTPases for actin remodeling (PMID:24623723). Loss of TIM4 selectively impairs apoptotic-cell binding by resident peritoneal macrophages and, in combination with MFG-E8 deficiency, drives autoantibody production, linking defective efferocytosis to autoimmunity (PMID:20421466, PMID:22723547). Beyond corpse clearance, TIM4 is the endogenous ligand for TIM-1 on T cells and costimulates their proliferation through LAT/Akt/ERK signaling (PMID:15793576, PMID:18354194), shapes anti-tumor immunity by sequestering PS-exposing CD8+ T cells and by enabling cross-presentation through F-actin-dependent delay of phagosomal acidification (PMID:34115989, PMID:38607919), and reprograms efferocytic macrophages toward an IL-10-secreting, anti-fibrotic state that restrains hepatic stellate cell activation in MASH (PMID:40929246). TIM4 additionally restrains inflammation through LKB1/AMPKα-mediated autophagic suppression of the NLRP3 inflammasome (PMID:31263038) and influences macrophage cholesterol homeostasis via the Insig1–SCAP–SREBP2 axis (PMID:36450259).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 High

    Established the first functional partner for TIM4 by identifying it as the endogenous TIM-1 ligand, framing TIM4 as a regulator of T cell proliferation before its efferocytosis role was known.

    Evidence Ig-fusion protein binding and T cell costimulation assays with in vivo administration

    PMID:15793576

    Open questions at the time
    • Did not define the molecular basis of TIM4–TIM-1 binding
    • Endogenous expression context of the interaction not resolved
  2. 2007 High

    Answered what TIM4 recognizes on dying cells, defining it as a PS receptor whose IgV domain directly binds PS to mediate engulfment, with blockade causing autoantibodies in vivo.

    Evidence Expression cloning, fibroblast gain-of-function engulfment, antibody blockade in vitro and in vivo; phospholipid binding plus PS-pocket mutagenesis

    PMID:17960135 PMID:18082433

    Open questions at the time
    • Did not establish how PS binding couples to internalization
    • Co-receptor requirements unaddressed
  3. 2009 High

    Resolved whether TIM4 signals directly, showing it acts purely as a PS tether—cytoplasmic tail and transmembrane domain dispensable—implying obligate partner receptors for uptake.

    Evidence Cytoplasmic-tail deletion, GPI-anchor replacement, siRNA/knockout of canonical engulfment pathways, cytoskeleton disruption

    PMID:19217291

    Open questions at the time
    • Identity of the downstream signaling co-receptor not yet defined
    • Mechanism linking tethering to cytoskeletal engagement unknown
  4. 2010 High

    Defined the physiological cellular role through genetic loss-of-function, showing TIM4 is selectively required for apoptotic (not necrotic or opsonized) cell clearance by resident peritoneal macrophages.

    Evidence Tim4-/- mice; in vitro and in vivo phagocytosis assays; imaging of receptor capping

    PMID:20421466

    Open questions at the time
    • Did not identify the partner receptor mediating engulfment
    • Cell-type specificity of requirement only partly explored
  5. 2014 High

    Identified the missing engulfment partner, establishing a two-step model in which TIM4 captures apoptotic cells and MERTK then drives internalization, and defined integrin/Src/FAK/Rho-GTPase signaling for actin remodeling.

    Evidence Tim4-null and MerTK-null macrophages, Ba/F3 reconstitution, phosphorylation assays; single-particle imaging of TIM4/β1 integrin association with signaling knockdowns

    PMID:24515440 PMID:24623723

    Open questions at the time
    • Physical basis of TIM4–MERTK association not yet mapped
    • Relative contributions of integrin vs MERTK routes unresolved
  6. 2014 High

    Provided the structural logic of PS recognition, defining one Ca2+ pocket plus weak ionic sites that make TIM4 uniquely PS-density-sensitive, enabling discrimination of apoptotic cells from activated T cells.

    Evidence Interfacial X-ray scattering, molecular dynamics, PS-density binding assays

    PMID:24706780

    Open questions at the time
    • Density sensitivity not directly tied to in vivo target selection
    • Structure of the full receptor in membrane context not determined
  7. 2014 Medium

    Extended TIM4 beyond clearance into immune regulation and tissue-specific phagosome control, linking it to AMPKα-driven autophagic degradation of tumor antigen and to phagosome stabilization during neuronal corpse removal.

    Evidence Co-IP of TIM-4/AMPKα with autophagy/antigen-presentation assays; zebrafish live imaging with genetic loss-of-function

    PMID:24315994 PMID:24898390

    Open questions at the time
    • AMPKα interaction shown by single-lab Co-IP
    • Phagosome-stabilization mechanism not molecularly defined
  8. 2019 High

    Refined the cooperative model by showing TIM4 enhancement of TAM-receptor efferocytosis is macrophage-population-specific and that TIM4 and MERTK signal through partly distinct downstream pathways.

    Evidence Single-TAM-receptor cell lines, Tim4-null macrophages across multiple primary populations, pathway inhibitors and MERTK domain mutagenesis in reconstituted Ba/F3 cells

    PMID:28768810 PMID:30846565

    Open questions at the time
    • Determinants of population specificity not identified
    • Direct vs indirect pathway contributions incompletely separated
  9. 2020 Medium

    Mapped the physical TIM4–MERTK interaction to the TIM4 IgV and MERTK fibronectin III domains, providing the molecular basis for cooperative efferocytosis.

    Evidence Immunoprecipitation, proximity ligation, and domain-mapping competition with soluble GST-MertkFnIII

    PMID:32640697

    Open questions at the time
    • Single-lab interaction mapping
    • Stoichiometry and structural detail of the complex unknown
  10. 2021 Medium

    Connected TIM4 PS recognition to anti-tumor immune suppression, showing cavity macrophages sequester PS-exposing CD8+ T cells, and that TIM4 on cDC1 drives tumor-antigen cross-presentation.

    Evidence In vivo TIM4 blockade in immunotherapy models; conditional cDC1 TIM4 deletion with cross-presentation and tumor-progression readouts

    PMID:33854047 PMID:34115989

    Open questions at the time
    • Single-lab in vivo models
    • Direct versus indirect effects on T cell fate not fully separated
  11. 2024 Medium

    Established a mechanism for TIM4-driven cross-presentation, showing TIM4 engulfment nucleates F-actin around phagosomes to delay acidification and preserve antigen for CD8+ T cell priming.

    Evidence Live imaging of phagosome maturation, F-actin/v-ATPase recruitment assays, cross-presentation assays, in vivo TIM4-knockout tumor model

    PMID:38607919

    Open questions at the time
    • Molecular trigger linking TIM4 to F-actin nucleation undefined
    • Single-lab study
  12. 2025 High

    Defined a therapeutically relevant TIM4 axis in liver disease, showing TIM4-mediated efferocytosis reprograms Kupffer cells to secrete IL-10 that suppresses profibrotic hepatic stellate cells in MASH.

    Evidence Kupffer-cell Timd4 conditional knockout and restoration, TIM4+ cell therapy, neutralizing antibodies, macrophage-HSC co-culture, IL-10/IL-10R assays in mouse and human MASH

    PMID:40929246

    Open questions at the time
    • Upstream control of efferocytosis-to-IL-10 reprogramming unresolved
    • Human translation of cell therapy not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TIM4's diverse non-PS ligand recognition (bacterial particles, viral glycoproteins, carbon nanotubes, microplastics) and its many reported intracellular partners (LKB1/AMPKα, SCAP/Insig1, ANXA2, αvβ3 integrin) are mechanistically integrated with its tether-only signaling architecture remains unresolved.
  • Most non-canonical interactions rest on single-lab Co-IP
  • How a tail-dispensable receptor couples to intracellular signaling partners is unexplained
  • Relative physiological weight of each pathway unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 4 GO:0008289 lipid binding 3 GO:0048018 receptor ligand activity 2 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-5357801 Programmed Cell Death 2
Partners
ANXA2HAVCR1HAVCR2ITGAVITGB1MERTKPRKAA1STK11

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Tim4 (TIMD4) was identified as a phosphatidylserine (PS) receptor: its immunoglobulin domain directly binds PS on apoptotic cells and on expelled erythroid nuclei, mediating their phagocytic engulfment. Expression in fibroblasts conferred engulfment activity, and anti-Tim4 monoclonal antibody blocked engulfment in vitro and in vivo, causing autoantibody development in mice. Expression cloning; monoclonal antibody inhibition assay; fibroblast gain-of-function engulfment assay; in vivo antibody injection Nature High 17960135
2007 TIM-4 (and TIM-1) specifically bind PS on apoptotic cells (but no other phospholipid tested) via a conserved cavity in the IgV domain. Point mutations abolishing this cavity eliminated PS binding and phagocytosis. TIM-4-expressing peritoneal macrophages and transfected cells efficiently phagocytosed apoptotic cells, blocked by anti-TIM-4 mAbs mapping to the binding cavity. Phospholipid binding assays; site-directed mutagenesis of PS-binding cavity; phagocytosis assay with transfected cells; mAb epitope mapping Immunity High 18082433
2005 TIM-4 (expressed on antigen-presenting cells) is the endogenous ligand for TIM-1 (expressed on T cells). TIM-4-Ig fusion protein costimulated T cell proliferation via CD3/CD28; in vivo administration of soluble TIM-1-Ig or TIM-4-Ig caused T cell hyperproliferation, establishing TIM-1/TIM-4 interaction as a regulator of T cell proliferation. Soluble Ig-fusion protein binding assays; in vitro T cell proliferation costimulation assay; in vivo administration of fusion proteins Nature immunology High 15793576
2009 TIM-4 functions as a PS tethering receptor without direct intracellular signaling: a TIM-4 mutant lacking its entire cytoplasmic tail still promoted apoptotic cell engulfment comparably to wild-type, and replacement of the transmembrane domain with a GPI anchor also supported engulfment. TIM-4-mediated uptake was independent of the ELMO1/Dock180/Rac and GULP signaling pathways, yet required an intact cytoskeleton. Dominant-negative mutants; siRNA knockdown of signaling components; knockout cell lines; cytoplasmic-tail deletion and GPI-anchor replacement constructs; cytoskeleton disruption drugs Current biology High 19217291
2014 Tim4 and MerTK cooperate in a two-step mechanism for efferocytosis by resident peritoneal macrophages: Tim4 acts as a PS-binding tether that captures apoptotic cells, and this Tim4-dependent binding is required for subsequent MerTK-mediated tyrosine phosphorylation and internalization. Tim4-null macrophages had reduced binding and engulfment; MerTK-null macrophages bound but failed to engulf; Tim4 + MerTK co-expression in Ba/F3 cells reconstituted full engulfment activity. Neutralizing antibody inhibition; Tim4-null and MerTK-null macrophages; Ba/F3 reconstitution with Tim4 and/or MerTK; tyrosine phosphorylation assay Molecular and cellular biology High 24515440
2014 TIM4-driven phagocytosis requires integrin co-receptor activation: TIM4 associates with β1 integrins upon receptor clustering (single-particle detection), and phagocytosis depends on Src-family kinases, focal adhesion kinase (FAK), PI(3,4,5)P3 accumulation, Vav3 recruitment, and synergistic action of RhoA, Rac1, and Rac2. TIM4 operates independently of lactadherin as a bridging molecule. TIM4-/- bone marrow-derived macrophages vs. wild-type; heterologous expression in AD293 cells; gene silencing/ablation of signaling intermediates; single-particle detection of TIM4/β1 integrin association Molecular biology of the cell High 24623723
2014 TIM-4 on tumor-associated myeloid cells directly interacts with AMPKα1 and activates autophagy-mediated degradation of ingested tumor cells, leading to reduced antigen presentation and impaired CTL responses. Blockade of the TIM-4–AMPKα1–autophagy pathway enhanced antitumor CTL responses. Co-immunoprecipitation of TIM-4 and AMPKα1; autophagy assays; antigen presentation assays; tumor models with TIM-4 blockade Immunity Medium 24315994
2014 Using interfacial X-ray scattering, molecular dynamics simulations, and membrane binding assays, Tim4 was shown to possess one Ca2+-coordinated primary PS binding pocket (IgV domain) plus four weaker ionic interaction sites, making Tim4 sensitive to PS surface density. This organization allows differential recognition of apoptotic cells (high PS) versus activated T cells (intermediate PS), unlike TIM-1 and TIM-3 which are less PS-density-sensitive. Interfacial X-ray scattering; molecular dynamics simulation; PS membrane-binding assays with varying PS density Proceedings of the National Academy of Sciences of the United States of America High 24706780
2008 TIM-4 expressed on APCs specifically phosphorylates TIM-1 on T cells and induces signaling through LAT, Akt, and ERK1/2, promoting T cell expansion by enhancing cell division and reducing apoptosis. Anti-TIM-4 monoclonal antibodies; phosphorylation assays for TIM-1, LAT, Akt, ERK1/2; T cell proliferation and apoptosis assays Journal of immunology Medium 18354194
2019 Tim4 alone does not support efferocytosis but enhances TAM-receptor (MERTK/Tyro3/Axl)-dependent efferocytosis in specific macrophage populations. ProS/Gas6 bridging molecules bind PtdSer and TAM receptors; Gas6 binds Axl strongly but ProS does not. Tim4 enhancement of TAM-mediated efferocytosis is population-specific: required by resident peritoneal macrophages, Kupffer cells, and CD169+ skin macrophages, but not by thioglycollate-elicited macrophages or primary microglia. NIH3T3-based cell lines expressing single TAM receptors; Tim4-null macrophages; multiple primary macrophage populations; recombinant ProS/Gas6 with Kd measurements Proceedings of the National Academy of Sciences of the United States of America High 28768810
2019 TIM4 and MERTK signal through distinct pathways: efferocytosis by resident peritoneal macrophages requires MEK/ERK, AKT, FAK, and STAT6 (but not NF-κB or STAT5), while MERTK-mediated proliferation in response to apoptotic cells additionally requires NF-κB and STAT5. The juxtamembrane and C-terminal regions of MERTK have redundant roles in efferocytosis. TIM4 and MERTK together enable apoptotic-cell-induced Ba/F3 cell proliferation in a PtdSer-dependent manner. Pathway inhibitors; MERTK domain mutagenesis; reconstituted Ba/F3 cell system with MERTK + TIM4; phosphorylation assays The Journal of biological chemistry Medium 30846565
2020 Tim-4 physically associates with Mertk via an interaction between the IgV domain of Tim-4 and the fibronectin type-III domain of Mertk. This interaction is required for Mertk to enhance Tim-4-mediated efferocytosis, as a soluble GST-MertkFnIII fragment that disrupts the interaction abolishes the enhancement. Immunoprecipitation; immunofluorescence and proximity ligation assay; domain-mapping with soluble GST-MertkFnIII competitor Cells Medium 32640697
2014 In zebrafish microglia, TIM-4 is required specifically for phagosome stabilization during engulfment of dying neurons, while BAI1 controls phagosome formation and cargo transport. Loss of TIM-4 alone allows recognition of apoptotic targets but causes distinct clearance defects; combined BAI1 and TIM-4 activity is required for complete neuronal corpse removal. Live imaging of zebrafish embryo brain; genetic loss-of-function (TIM-4 and BAI1 morpholino/mutant); quantification of phagocytic stages Nature communications Medium 24898390
2021 Tim-4+ cavity-resident macrophages sequester viable cytotoxic CD8+ T cells away from tumor targets and suppress their proliferation through PS recognition, since anti-tumor CD8+ T cells upregulate PS exposure. Tim-4 blockade abrogates this sequestration and restores anti-tumor CD8+ T cell efficacy in mouse models. Flow cytometry of pleural effusions/ascites; in vivo Tim-4 blockade in anti-PD-1 and adoptive T cell therapy mouse models; PS exposure measurement on CD8+ T cells Cancer cell Medium 34115989
2016 Residues within the PS-binding pocket of the TIM-4 IgV domain (murine and human) are required for Ebola virus (EBOV) pseudovirion binding and entry. Mutagenesis identified 8 mTIM-4 and 14 hTIM-4 IgV domain residues critical for virion binding and internalization, with TIM-4-specific residues beyond those shared with TIM-1. Site-directed mutagenesis of TIM-4 IgV domain residues; VSV pseudovirion bearing EBOV glycoprotein entry assays; virus binding assays Journal of virology Medium 27122575
2021 Tim4 recognizes multi-walled carbon nanotubes (MWCNTs) through aromatic-aromatic interactions between aromatic residues in the extracellular IgV domain and the carbon crystal surface. CRISPR-Cas9 deletion of Tim4 (but not Tim1) in peritoneal macrophages impaired MWCNT recognition and phagocytosis, and reduced granuloma formation in vivo. Docking simulations confirmed spatiotemporally stable interfaces. Targeted receptor screening; molecular docking simulation; CRISPR-Cas9 Tim4 deletion; phagocytosis assays; in vivo mesothelial MWCNT exposure model Cell reports Medium 33567275
2023 Tim4 binds polystyrene (PS) microparticles through extracellular aromatic cluster interactions (aromatic-aromatic), the same cluster involved in MWCNT recognition. Genetic deletion of Tim4 reduced macrophage engulfment of PS microplastics. PS microparticles competitively blocked Tim4-mediated efferocytosis of apoptotic cells, but PS microparticle engulfment did not activate NLRP3/IL-1β unlike MWCNTs. Tim4 knockout macrophages; competitive efferocytosis assay; cytokine secretion assays; comparison with MWCNT responses The Science of the total environment Medium 36871719
2019 Tim-4 in macrophages inhibits NLRP3 inflammasome activation via the LKB1/AMPKα pathway: Tim-4 physically interacts with LKB1 and AMPKα (shown by co-IP), promoting AMPKα phosphorylation and AMPKα-mediated autophagy-dependent degradation of NLRP3 components, reducing IL-1β and IL-18 release. The PS-binding IgV domain of Tim-4 is required for this LKB1/AMPKα interaction. Co-immunoprecipitation of Tim-4, LKB1, and AMPKα; Tim-4 knockout mice; NLRP3 inflammasome activation assays; autophagy assays; IgV domain mutants Journal of immunology Medium 31263038
2022 Tim-4 disrupts the Insig1-SCAP interaction in macrophages, promoting SCAP-SREBP2 complex translocation to the Golgi apparatus and upregulation of cholesterol biosynthesis, which in turn limits type I IFN signaling. Tim-4 deficiency boosts IFN signaling and decreases viral load. Tim-4 knockout mice; co-immunoprecipitation of Insig1 and SCAP; SREBP2 activation assays; IFN pathway reporter assays; viral infection models Cell reports Medium 36450259
2020 Tim-4 functions as a scavenger receptor for phagocytosis of exogenous bacterial particles (E. coli and S. aureus bioparticles) via a phosphatidylserine-independent mechanism. The IgV domain and mucin domain of Tim-4 (but not the cytoplasmic tail) are required for this scavenging activity. A PS-binding-deficient Tim-4 mutant (Tim-4AAA) still promoted bacterial particle phagocytosis. Tim-4 overexpression enhanced LPS binding. Tim-4 overexpression and knockout cell lines; domain deletion mutants; PS-binding-deficient mutant (Tim-4AAA); Anxa5 competition assay; LPS binding assay Cell death & disease Medium 32703939
2015 TIM-4 promotes non-small-cell lung cancer cell growth and proliferation through its RGD motif by interacting with αvβ3 integrin; RGD motif mutation abolishes TIM-4-induced proliferation in vitro and in xenograft models. Co-IP confirmed TIM-4–αvβ3 integrin interaction. Co-immunoprecipitation; RGD motif site-directed mutagenesis; cell proliferation assays (CCK-8, EdU); xenograft tumor model British journal of cancer Medium 26512878
2022 N-glycosylation of TIM-4 at Asn291 stabilizes the protein; removal of this glycosylation increases TIM-4 susceptibility to ER-localized ubiquitin ligase-mediated ERAD degradation, decreasing TIM-4 surface expression and suppressing TIM-4-mediated metastasis in NSCLC cells. Site-directed mutagenesis of N-glycosylation site (Asn291); protein stability/degradation assays; ERAD pathway analysis; cell migration/invasion assays Frontiers in oncology Medium 35433445
2023 TIM-4 promotes mitochondrial fusion and oxidative phosphorylation in lung cancer cells via the ANXA2/PI3K/AKT/OPA1 axis: TIM-4 interacts with ANXA2 (co-IP), activating PI3K/AKT signaling to increase L-OPA1 protein expression, promoting mitochondrial fusion and OXPHOS-dependent proliferation. Inhibiting OXPHOS reversed TIM-4-induced proliferation. Co-immunoprecipitation of TIM-4 and ANXA2; PI3K/AKT pathway inhibitors; mitochondrial morphology assays; OPA1 expression analysis; OXPHOS inhibitor rescue experiments Cell death & disease Medium 36806050
2010 Tim-4 deficiency in resident peritoneal macrophages (rPMs) significantly impairs binding and engulfment of apoptotic cells in vitro and in vivo, but does not affect phagocytosis of necrotic cells or opsonized targets. Tim-4 rapidly forms punctate caps upon contact with apoptotic cells. Tim-4 deficiency does not impair marginal zone trapping of apoptotic cells, tingible body macrophage clearance, or germinal center formation, but causes increased peritoneal cellularity and altered macrophage responses to LPS and TNF-α. Tim-4-/- mice; in vitro and in vivo phagocytosis assays; fluorescence microscopy of Tim-4 redistribution; peritoneal cellularity analysis; LPS/TNF-α response assays Proceedings of the National Academy of Sciences of the United States of America High 20421466
2012 Tim4 deficiency specifically impairs resident peritoneal macrophage (but not thioglycollate-elicited macrophage) engulfment of apoptotic cells. Double deficiency of Tim4 and MFG-E8 causes age-dependent autoantibody production in female C57BL/6 mice, synergistically disrupting apoptotic cell clearance and immune homeostasis. Tim4-/- and Tim4-/-MFG-E8-/- double-knockout mice; peritoneal and thioglycollate-elicited macrophage engulfment assays; autoantibody measurement; anti-TNFα and pristane treatment International immunology High 22723547
2024 TIM4-mediated engulfment by large peritoneal macrophages induces nucleation of F-actin around nascent phagosomes, delaying vacuolar ATPase recruitment, phagosomal acidification, and cargo degradation, thereby prolonging antigen integrity and facilitating cross-presentation of tumor-associated antigens to CD8+ T cells. In vivo, TIM4 deletion blunts early anti-tumor CD8+ T cell induction and accelerates peritoneal tumor progression. Live imaging of phagosome formation; F-actin/v-ATPase recruitment assays; cross-presentation assays; TIM4-knockout in vivo ovarian tumor model; PS-coated artificial targets Cell reports Medium 38607919
2021 TIM4 on lung-resident cDC1 dendritic cells mediates capture and phagocytosis of cell-associated tumor antigens. Loss of TIM4 by conditional cDC1 deletion or TIM4 blockade impairs activation of tumor-specific CD8+ T cells and promotes lung tumor progression. Conditional TIM4 deletion in cDC1; TIM4 receptor blockade; cross-presentation and CD8+ T cell activation assays; lung tumor progression in mice Nature communications Medium 33854047
2011 TIM-4 inhibits naive T cell activation through a ligand other than TIM-1 (TIM-1-independent pathway), while it promotes expansion of pre-activated T cells. In vivo anti-TIM-4 antibody blockade suppressed T cell-mediated inflammatory responses despite enhanced antigen-specific T cell generation. TIM-4-Ig fusion protein stimulation of naive vs. pre-activated T cells; in vivo anti-TIM-4 blockade; adoptive transfer of primed T cells International immunology Medium 18367551
2021 Blocking the PS receptor Tim4 in adipose tissue macrophages inhibits lysosomal activation and the release of post-prandial high-density lipoprotein cholesterol following a high-fat meal. This implicates Tim4-dependent lysosomal function in resident adipose tissue macrophage regulation of cholesterol transport. Anti-Tim4 antibody blockade; chloroquine (lysosomal inhibitor) comparison; single-cell RNA sequencing; protected bone marrow chimeras; clodronate cell depletion; post-prandial lipid measurements Nature communications Medium 34290249
2025 Efferocytosis by liver macrophages via TIM4 is impaired in MASH, driving fibrosis. TIM4 deletion or neutralization in Kupffer cells reduces apoptotic hepatocyte clearance and accelerates profibrotic hepatic stellate cell (HSC) activation. Genetic restoration of macrophage Timd4 or cell therapy with TIM4+ macrophages enhances clearance and reduces fibrosis. Mechanistically, TIM4-mediated efferocytosis reprograms macrophages to secrete IL-10, which activates the IL-10 receptor on HSCs to suppress their profibrotic activation. Timd4 conditional knockout in Kupffer cells; Timd4 genetic restoration; TIM4+ cell therapy; anti-TIM4 neutralizing antibodies; ex vivo macrophage-HSC co-culture; IL-10/IL-10R pathway assays Science translational medicine High 40929246
2016 Tim-4 inhibits NO production and iNOS expression in LPS- or IFN-γ-stimulated macrophages by suppressing NF-κB p65 phosphorylation (for LPS) and Jak2/Stat1 phosphorylation (for IFN-γ). Conversely, Tim-4 blockade promotes NF-κB and Jak2/Stat1 signaling and enhances NO secretion. Tim-4 overexpression and antibody blockade; Griess reaction for NO; Western blot for NF-κB/Jak2/Stat1 phosphorylation; NF-κB inhibitor rescue PloS one Medium 25905790
2011 Tim-4 inhibits naive T cell activation and Th17 differentiation via a Tim-1-independent receptor; both the IgV domain and the mucin domain of Tim-4 are required for these inhibitory effects, mediated at least in part through inhibition of ERK signaling. Tim-4 IgV-only and mucin-only fusion protein domain constructs; ERK phosphorylation assays; Th17 polarization assays; proliferation and cytokine assays Immunology Medium 21463297
2004 SMUCKLER/TIM4 expression in the spleen is downregulated by LTα or LTβ deficiency (identified by expression profiling of knockout spleens). In situ hybridization showed expression in stromal cells predominantly in the marginal zone. Unlike TIM1 and TIM3, TIM4 lacks a tyrosine phosphorylation motif in its intracellular domain and is not expressed by bone marrow-derived cells. Gene expression profiling of LTα-/- and LTβ-/- mice; in situ hybridization; expression cloning/structural analysis European journal of immunology Low 14768054
2016 TIM-4 interacts with TIM-3 on the surface of polarized Th1 cells, forming a TIM3-TIM4 complex that induces Th1 cell apoptosis by increasing p300 phosphorylation, which upregulates Fas ligand expression and triggers apoptosis. Detection of TIM3-TIM4 surface complex by flow cytometry; p300 phosphorylation assay; FasL ChIP, RT-PCR, and Western blot; Th1 cell apoptosis flow cytometry Immunologic research Low 26403707

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Identification of Tim4 as a phosphatidylserine receptor. Nature 927 17960135
2007 TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 536 18082433
2018 Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression. The Journal of experimental medicine 301 29789388
2005 TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation. Nature immunology 295 15793576
2014 Distinct roles for BAI1 and TIM-4 in the engulfment of dying neurons by microglia. Nature communications 171 24898390
2021 Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T cell immunity. Cancer cell 162 34115989
2010 Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages. Proceedings of the National Academy of Sciences of the United States of America 134 20421466
2009 The phosphatidylserine receptor TIM-4 does not mediate direct signaling. Current biology : CB 128 19217291
2007 TIM-4 expressed by mucosal dendritic cells plays a critical role in food antigen-specific Th2 differentiation and intestinal allergy. Gastroenterology 127 17915221
2020 IL-6 promotes metastasis of non-small-cell lung cancer by up-regulating TIM-4 via NF-κB. Cell proliferation 120 32020709
2014 Tim4- and MerTK-mediated engulfment of apoptotic cells by mouse resident peritoneal macrophages. Molecular and cellular biology 117 24515440
2013 TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance. Immunity 115 24315994
2014 The phosphatidylserine receptor TIM4 utilizes integrins as coreceptors to effect phagocytosis. Molecular biology of the cell 101 24623723
2008 TIM-4 expressed on APCs induces T cell expansion and survival. Journal of immunology (Baltimore, Md. : 1950) 98 18354194
2008 Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)-1/TIM4 interaction as a therapeutic strategy in a dendritic cell-induced peanut allergy model. The Journal of allergy and clinical immunology 91 18547633
2019 TIM-4 interference in Kupffer cells against CCL4-induced liver fibrosis by mediating Akt1/Mitophagy signalling pathway. Cell proliferation 83 31755616
2010 TIM-4, a receptor for phosphatidylserine, controls adaptive immunity by regulating the removal of antigen-specific T cells. Journal of immunology (Baltimore, Md. : 1950) 78 21037090
2014 T-cell immunoglobulin and mucin domain 4 (TIM-4) signaling in innate immune-mediated liver ischemia-reperfusion injury. Hepatology (Baltimore, Md.) 74 25066922
2017 Mouse macrophages show different requirements for phosphatidylserine receptor Tim4 in efferocytosis. Proceedings of the National Academy of Sciences of the United States of America 64 28768810
2018 RETRACTED: Tim-4 promotes the growth of colorectal cancer by activating angiogenesis and recruiting tumor-associated macrophages via the PI3K/AKT/mTOR signaling pathway. Cancer letters 63 30118845
2014 Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4. Proceedings of the National Academy of Sciences of the United States of America 62 24706780
2008 Bimodal regulation of T cell-mediated immune responses by TIM-4. International immunology 62 18367551
2017 Role of TIM-4 in exosome-dependent entry of HIV-1 into human immune cells. International journal of nanomedicine 60 28740388
2019 MERTK tyrosine kinase receptor together with TIM4 phosphatidylserine receptor mediates distinct signal transduction pathways for efferocytosis and cell proliferation. The Journal of biological chemistry 57 30846565
2021 TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses. Nature communications 53 33854047
2016 Blockade of Tim-1 and Tim-4 Enhances Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice. Arteriosclerosis, thrombosis, and vascular biology 52 26821944
2012 Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity. International immunology 50 22723547
2011 The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury. Journal of the American Society of Nephrology : JASN 50 21355054
2007 Staphylococcal enterotoxin B increases TIM4 expression in human dendritic cells that drives naïve CD4 T cells to differentiate into Th2 cells. Molecular immunology 50 17439824
2021 Anti-Tim4 Grafting Strongly Hydrophilic Metal-Organic Frameworks Immunoaffinity Flake for High-Efficiency Capture and Separation of Exosomes. Analytical chemistry 49 33851819
2015 Tim-3 and Tim-4 as the potential targets for antitumor therapy. Human vaccines & immunotherapeutics 49 26211834
2012 Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas. Cancer immunology, immunotherapy : CII 46 23143694
2019 Tim-4 Inhibits NLRP3 Inflammasome via the LKB1/AMPKα Pathway in Macrophages. Journal of immunology (Baltimore, Md. : 1950) 44 31263038
2004 SMUCKLER/TIM4 is a distinct member of TIM family expressed by stromal cells of secondary lymphoid tissues and associated with lymphotoxin signaling. European journal of immunology 44 14768054
2016 Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry. Journal of virology 42 27122575
2020 Tim-4 in Health and Disease: Friend or Foe? Frontiers in immunology 41 32300343
2023 TIM-4 orchestrates mitochondrial homeostasis to promote lung cancer progression via ANXA2/PI3K/AKT/OPA1 axis. Cell death & disease 40 36806050
2022 A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types. Cancer immunology research 40 36122412
2015 TIM-4 promotes the growth of non-small-cell lung cancer in a RGD motif-dependent manner. British journal of cancer 39 26512878
2012 TIM-4, expressed by medullary macrophages, regulates respiratory tolerance by mediating phagocytosis of antigen-specific T cells. Mucosal immunology 38 23149665
2013 Interruption of dendritic cell-mediated TIM-4 signaling induces regulatory T cells and promotes skin allograft survival. Journal of immunology (Baltimore, Md. : 1950) 37 24038092
2007 Apoptotic PS to phagocyte TIM-4: eat me. Immunity 37 18093535
2022 TIM-4 in macrophages contributes to nasal polyp formation through the TGF-β1-mediated epithelial to mesenchymal transition in nasal epithelial cells. Frontiers in immunology 35 35990621
2021 Role of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels. Nature communications 35 34290249
2017 TIM-4 Identifies IFN-γ-Expressing Proinflammatory B Effector 1 Cells That Promote Tumor and Allograft Rejection. Journal of immunology (Baltimore, Md. : 1950) 34 28848066
2011 Glioma-derived T cell immunoglobulin- and mucin domain-containing molecule-4 (TIM4) contributes to tumor tolerance. The Journal of biological chemistry 31 21896488
2019 Characterization of Subpopulations of Chicken Mononuclear Phagocytes That Express TIM4 and CSF1R. Journal of immunology (Baltimore, Md. : 1950) 30 30626692
2021 Tim4 recognizes carbon nanotubes and mediates phagocytosis leading to granuloma formation. Cell reports 29 33567275
2020 Mertk Interacts with Tim-4 to Enhance Tim-4-Mediated Efferocytosis. Cells 27 32640697
2009 Specific immunotherapy suppresses Th2 responses via modulating TIM1/TIM4 interaction on dendritic cells. Allergy 27 20028372
2017 TIM4-TIM1 interaction modulates Th2 pattern inflammation through enhancing SIRT1 expression. International journal of molecular medicine 26 28949386
2013 TIM-4 has dual function in the induction and effector phases of murine arthritis. Journal of immunology (Baltimore, Md. : 1950) 26 24068667
2018 TIM‑4 blockade of KCs combined with exogenous TGF‑β injection helps to reverse acute rejection and prolong the survival rate of mice receiving liver allografts. International journal of molecular medicine 22 29620252
2018 Hepatic Ischemic Preconditioning Alleviates Ischemia-Reperfusion Injury by Decreasing TIM4 Expression. International journal of biological sciences 21 30123068
2023 Tim4, a macrophage receptor for apoptotic cells, binds polystyrene microplastics via aromatic-aromatic interactions. The Science of the total environment 20 36871719
2020 Tim-4 functions as a scavenger receptor for phagocytosis of exogenous particles. Cell death & disease 20 32703939
2018 Association between the TIMD4-HAVCR1 variants and serum lipid levels, coronary heart disease and ischemic stroke risk and atorvastatin lipid-lowering efficacy. Bioscience reports 20 29208769
2015 Tim-4 Inhibits NO Generation by Murine Macrophages. PloS one 20 25905790
2011 Tim-4 inhibition of T-cell activation and T helper type 17 differentiation requires both the immunoglobulin V and mucin domains and occurs via the mitogen-activated protein kinase pathway. Immunology 20 21463297
2022 Tim-4 reprograms cholesterol metabolism to suppress antiviral innate immunity by disturbing the Insig1-SCAP interaction in macrophages. Cell reports 19 36450259
2016 Essential Roles of TIM-1 and TIM-4 Homologs in Adaptive Humoral Immunity in a Zebrafish Model. Journal of immunology (Baltimore, Md. : 1950) 19 26792807
2016 Histone acetyltransferease p300 modulates TIM4 expression in dendritic cells. Scientific reports 19 26899911
2015 Disruption of TIM-4 in dendritic cell ameliorates hepatic warm IR injury through the induction of regulatory T cells. Molecular immunology 19 25771178
2012 Genetic variation and significant association of polymorphism rs7700944 G>A of TIM-4 gene with rheumatoid arthritis susceptibility in Chinese Han and Hui populations. International journal of immunogenetics 18 22353209
2018 Probiotics SOD inhibited food allergy via downregulation of STAT6-TIM4 signaling on DCs. Molecular immunology 17 30216839
2016 Tim-4 protects mice against lipopolysaccharide-induced endotoxic shock by suppressing the NF-κB signaling pathway. Laboratory investigation; a journal of technical methods and pathology 17 27617399
2024 Tim4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis. Cell reports 15 38607919
2022 Function and characteristics of TIM‑4 in immune regulation and disease (Review). International journal of molecular medicine 15 36524355
2016 TIM-4 is differentially expressed in the distinct subsets of dendritic cells in skin and skin-draining lymph nodes and controls skin Langerhans cell homeostasis. Oncotarget 15 27224924
2025 IRG1/itaconate enhances efferocytosis by activating Nrf2-TIM4 signaling pathway to alleviate con A induced autoimmune liver injury. Cell communication and signaling : CCS 14 39910615
2024 Tim4 deficiency reduces CD301b+ macrophage and aggravates periodontitis bone loss. International journal of oral science 14 38418808
2017 The significance of TIMD4 expression in clear cell renal cell carcinoma. Medical molecular morphology 14 28631038
2015 Increased T cell immunoglobulin and mucin domain containing 4 (TIM-4) is negatively correlated with serum concentrations of interleukin-1β in type 2 diabetes. Journal of diabetes 14 25676395
2021 Platelet-derived extracellular vesicles are increased in sera of Alzheimer's disease patients, as revealed by Tim4-based assays. FEBS open bio 13 33345458
2020 The expression of Tim-1 and Tim-4 molecules in regulatory T cells in type 1 diabetes. Endocrine 13 31916216
2018 Cigarette Smoke Extract Promotes TIM4 Expression in Murine Dendritic Cells Leading to Th2 Polarization through ERK-Dependent Pathways. International archives of allergy and immunology 13 30522098
2022 N-Glycosylation at Asn291 Stabilizes TIM-4 and Promotes the Metastasis of NSCLC. Frontiers in oncology 12 35433445
2020 TIMD4 exhibits regulatory capability on the proliferation and apoptosis of diffuse large B-cell lymphoma cells via the Wnt/β-catenin pathway. The journal of gene medicine 12 32187802
2016 Expression of Tim4 in Glioma and its Regulatory Role in LN-18 Glioma Cells. Medical science monitor : international medical journal of experimental and clinical research 12 26741116
2013 Cockroach allergen Bla g 7 promotes TIM4 expression in dendritic cells leading to Th2 polarization. Mediators of inflammation 12 24204099
2016 TIM-4 is expressed on invariant NKT cells but dispensable for their development and function. Oncotarget 11 27662666
2014 TIM4 Regulates the Anti-Islet Th2 Alloimmune Response. Cell transplantation 11 24612609
2011 Role of TIM-4 in innate or adaptive immune response. North American journal of medical sciences 11 22558597
2025 Splenic CD169+Tim4+ Marginal Metallophilic Macrophages Are Essential for Wound Healing After Myocardial Infarction. Circulation 10 40289811
2025 Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction-associated steatohepatitis. Science translational medicine 10 40929246
2023 High Throughput and Noninvasive Exosomal PD-L1 Detection for Accurate Immunotherapy Response Prediction via Tim4-Functionalized Magnetic Core-Shell Metal-Organic Frameworks. Analytical chemistry 10 38011622
2021 Tim-4 expressing monocytes as a novel indicator to assess disease activity and severity of ulcerative colitis. Life sciences 10 33465392
2021 Identification of small compounds regulating the secretion of extracellular vesicles via a TIM4-affinity ELISA. Scientific reports 10 34188113
2018 Diverse roles of TIM4 in immune activation: implications for alloimmunity. Current opinion in organ transplantation 10 29189411
2015 TIM-1 rs41297579 G>A (-1454) and TIM-4 rs7700944 gene polymorphisms as possible risk factor for rheumatoid arthritis: relation to activity and severity. International journal of immunogenetics 10 25899833
2014 Flagellin modulates TIM4 expression in mast cells. Cell biology international 10 25044827
2014 Novel insights into Tim-4 function in autoimmune diseases. Autoimmunity 10 25470136
2017 Tim-4 expression increases in ischemic stroke patients and is associated with poor outcome. Journal of neuroimmunology 9 29233585
2012 A new development of FG-CC' siRNA blocking interaction of Tim-1 and Tim-4 can enhance DC vaccine against gastric cancer . Hepato-gastroenterology 9 22709877
2019 Inhibition of TIM-4 protects against cerebral ischaemia-reperfusion injury. Journal of cellular and molecular medicine 8 31774937
2016 Interaction of TIM4 and TIM3 induces T helper 1 cell apoptosis. Immunologic research 8 26403707
2016 Activation-Induced TIM-4 Expression Identifies Differential Responsiveness of Intestinal CD103+ CD11b+ Dendritic Cells to a Mucosal Adjuvant. PloS one 8 27379516
2024 TIMD4hiMHCⅡhi Macrophages Preserve Heart Function Through Retnla. JACC. Basic to translational science 7 39906591
2021 Enhancing the Endocytosis of Phosphatidylserine-Containing Liposomes through Tim4 by Modulation of Membrane Fluidity. Molecular pharmaceutics 7 34913345
2019 TIMD4 rs6882076 SNP Is Associated with Decreased Levels of Triglycerides and the Risk of Coronary Heart Disease and Ischemic Stroke. International journal of medical sciences 7 31337960

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