Affinage

CTLA4

Cytotoxic T-lymphocyte protein 4 · UniProt P16410

Length
223 aa
Mass
24.7 kDa
Annotated
2026-06-09
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CTLA-4 is an inducible inhibitory co-receptor that opposes CD28 costimulation to enforce peripheral T cell tolerance and restrain immune activation (PMID:7543139, PMID:1334116). Its expression is restricted to activated T cells through transcriptional induction following T cell activation, with PKC-dependent and cAMP/calcineurin-dependent inputs, and is largely absent from resting cells (PMID:8397258, PMID:8666782, PMID:12444128). CTLA-4 engages the B7-family ligands CD80 and CD86 on antigen-presenting cells, and ligation blocks CD28-dependent IL-2 production, IL-2 receptor expression, and cell cycle progression, enforcing the G1-to-S checkpoint via delayed p27kip1 re-expression rather than inducing apoptosis (PMID:8676075, PMID:7504292, PMID:11807776, PMID:10583602). Mechanistically, CTLA-4 attenuates proximal TCR signaling in cis when its ligands and the TCR are engaged on the same surface (PMID:10779742), and it transmits inhibitory signals by activating the ubiquitin ligase Itch to enhance ubiquitination of JunB and suppress cytokine mRNA accumulation (PMID:20417562). A central effector mechanism is transendocytosis: CTLA-4 physically removes CD80 and CD86 from APCs, with CD80-bound CTLA-4 routed to lysosomal degradation while CD86-bound CTLA-4 detaches in a pH-dependent manner and recycles for further rounds, identifying CD86 as the key regulatory target (PMID:35999394). CTLA-4 surface levels are tightly governed by intracellular trafficking through Rab5/Rab7/Rab11 compartments and LRBA-dependent recycling, where LRBA acts upstream of Rab11 to prevent CTLA-4 degradation (PMID:33960403). This function is essential in regulatory T cells, where CTLA-4 deficiency causes fatal lymphoproliferative autoimmunity and impairs Treg-mediated downregulation of CD80/CD86 on dendritic cells (PMID:18845758), and extends beyond T cells to B-1a B cells, where it maintains self-tolerance (PMID:33483505), and to soluble/secreted isoforms that suppress CD8+ T cells and APC activation (PMID:38053333, PMID:24928993). In vivo, CTLA-4 negatively regulates antitumor immunity, and its blockade drives tumor rejection, providing the basis for checkpoint immunotherapy (PMID:8596936, PMID:33588426).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1992 High

    Established that CTLA-4 is co-expressed with CD28 on activated T cells and cooperates to regulate B7-driven adhesion and activation, placing it in the costimulatory axis.

    Evidence Monoclonal antibody development, flow cytometry, and co-immobilized antibody stimulation in mixed lymphocyte culture

    PMID:1334116

    Open questions at the time
    • Did not distinguish inhibitory from activating function
    • No mechanism of signal transduction defined
  2. 1993 Medium

    Defined CTLA-4 as an activation-induced cell-surface monomeric glycoprotein under PKC-dependent and transcriptional control, explaining its inducible expression pattern.

    Evidence Metabolic and surface labeling, SDS-PAGE, Northern blot, PKC inhibitor and reporter assays; identification of B7-2 as a second ligand

    PMID:7504292 PMID:8397258 PMID:8666782

    Open questions at the time
    • Promoter elements only coarsely mapped
    • Transcription factors not identified
  3. 1996 High

    Demonstrated that CTLA-4 delivers a genuine inhibitory signal opposing CD28, blocking IL-2 production and proliferation without inducing apoptosis, defining its functional role as a brake.

    Evidence Anti-CTLA-4 cross-linking and ligation assays, cytokine ELISA, cell cycle analysis, exogenous IL-2 rescue, and in vivo tumor blockade in mice

    PMID:7543139 PMID:8596936 PMID:8676075

    Open questions at the time
    • Molecular basis of inhibition not resolved
    • Did not distinguish cell-intrinsic from cell-extrinsic effects
  4. 2000 Medium

    Showed that CTLA-4 inhibits proximal TCR signaling in cis, requiring co-engagement of TCR and CTLA-4 ligands on the same surface, defining the spatial logic of its inhibitory action.

    Evidence Surface-linked scFv on artificial APCs, tyrosine phosphorylation assays, and TCR transgenic T cells; CD28-independent inhibition via CD80/CD86 ligation

    PMID:10583602 PMID:10779742

    Open questions at the time
    • Specific phosphatases or signaling intermediates not identified
    • Single-lab engineered system
  5. 2002 High

    Established that CTLA-4 enforces the G1-to-S cell cycle checkpoint via p27kip1, and revealed expression and function in monocytes, broadening its regulatory scope.

    Evidence CTLA-4 knockout T cell cell-cycle analysis, cyclin/CDK and IL-2 readouts; flow cytometry and reporter assays in human monocytes and U937 cells

    PMID:11807776 PMID:11841692 PMID:12444128

    Open questions at the time
    • Link between surface CTLA-4 and p27kip1 regulation not mechanistically connected
    • Monocyte function based on single-lab data
  6. 2008 High

    Genetically established CTLA-4 as essential for Treg suppressive function and APC ligand downregulation, explaining the fatal autoimmunity of CTLA-4 deficiency.

    Evidence Foxp3-conditional CTLA-4 knockout with in vivo/in vitro suppression assays and CD80/CD86 flow cytometry on dendritic cells; osteoclastogenesis assays

    PMID:18203760 PMID:18845758

    Open questions at the time
    • Molecular mechanism of CD80/CD86 removal not yet defined here
    • Cell-intrinsic versus Treg-extrinsic contributions not fully separated
  7. 2010 Medium

    Identified the ubiquitin ligase Itch as a downstream effector of CTLA-4 inhibitory signaling, providing a biochemical pathway from CTLA-4 to cytokine suppression.

    Evidence Itch knockdown rescue, phosphorylation and JunB ubiquitination assays, cytokine mRNA analysis, and comparison of CTLA-4- and Itch-deficient mice

    PMID:20417562

    Open questions at the time
    • Upstream signal connecting CTLA-4 engagement to Itch activation not defined
    • Single-lab pathway
  8. 2014 Medium

    Resolved that CTLA-4 surface availability is dominated by intracellular trafficking, identifying adaptors and GTPases controlling its transport and residency.

    Evidence Co-immunoprecipitation, dominant-negative/constitutively active GTPase expression, and surface/internalization assays (TRIM, LAX, Rab8, ARF-1, PLD, AP1/2); soluble isoform characterization

    PMID:18468488 PMID:24928993 PMID:25538704

    Open questions at the time
    • Trafficking steps synthesized from review-level data
    • Hierarchy among trafficking factors not established
  9. 2021 High

    Established the LRBA–Rab11 recycling axis as the controller of CTLA-4 surface expression and stability, and extended CTLA-4 tolerance function to B-1a B cells.

    Evidence Dominant-negative/constitutively active Rab GTPases, LRBA knockdown/knockout with colocalization and degradation assays in HeLa/Jurkat; B cell-conditional knockout with autoantibody and transfer experiments; tumor Treg destabilization linked to glycolysis and CD28

    PMID:33483505 PMID:33588426 PMID:33960403

    Open questions at the time
    • Molecular details of LRBA action upstream of Rab11 not fully resolved
    • B-1a-specific tolerance mechanism distinct from T cell role not fully delineated
  10. 2022 High

    Provided reconstitution-level dissection of transendocytosis, showing divergent fates for CD80- versus CD86-bound CTLA-4 and identifying CD86 as the key regulatory target, with clinical mutations selectively disrupting CD86 capture.

    Evidence Transendocytosis, pH-dependent dissociation, ubiquitylation, and endosomal trafficking assays with functional analysis of clinical CTLA-4 mutations; antibody-driven lysosomal targeting and pH-sensitive antibody engineering

    PMID:31267017 PMID:35999394

    Open questions at the time
    • Ubiquitin ligase mediating CD80-bound CTLA-4 degradation not identified
    • Quantitative contribution of transendocytosis to in vivo suppression not measured
  11. 2023 Medium

    Demonstrated functional roles for soluble CTLA-4 isoforms in suppressing CD8+ T cells and showed that the CTLA-4 cytoplasmic tail can be engineered to improve CAR-T persistence, translating trafficking biology into therapeutic design.

    Evidence Isoform-specific antibody blockade in tumor models, CD8 suppression assays; CAR-CCT fusion engineering with trogocytosis, persistence, scRNA-seq, and in vivo leukemia readouts; MSC immunosuppression

    PMID:30087255 PMID:37500885 PMID:38053333

    Open questions at the time
    • Receptor/target of secreted sCTLA-4 not identified
    • MSC sCTLA-4 mechanism based on low-confidence single-lab data

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the ubiquitin ligase and signaling intermediates that route CD80-bound CTLA-4 to degradation, and the molecular target of secreted sCTLA-4, remain undefined.
  • No defined receptor for soluble CTLA-4 isoforms
  • Mechanism converting CTLA-4 ligand binding into intracellular inhibitory signaling incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 2 GO:0038024 cargo receptor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005764 lysosome 2 GO:0005768 endosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-1640170 Cell Cycle 1
Partners
CD28CD80CD86ITCHLRBARAB11

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 CTLA-4 delivers inhibitory signals opposing CD28 costimulation: cross-linking CTLA-4 together with TCR and CD28 strongly inhibits T cell proliferation and IL-2 secretion, and B7-2 on freshly explanted T cells can partially inhibit T cell proliferation via CTLA-4 interactions. Anti-CTLA-4 antibody cross-linking assay using purified T cells; comparison of proliferation and IL-2 secretion with and without CTLA-4 engagement The Journal of experimental medicine High 7543139
1992 CTLA-4 is coexpressed with CD28 on activated T lymphocytes and cooperatively regulates T cell adhesion and activation by B7; anti-CTLA-4 mAbs cooperate with anti-CD28 mAbs to inhibit T cell adhesion to B7 and block proliferation in mixed lymphocyte culture. Monoclonal antibody development; flow cytometry; co-immobilized antibody stimulation assays; mixed lymphocyte culture The Journal of experimental medicine High 1334116
1996 CTLA-4 ligation blocks CD28-dependent IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells; the primary effect is not induction of apoptosis; addition of exogenous IL-2 restores IL-2 receptor expression and T cell proliferation, indicating CTLA-4 does not block IL-2 responsiveness. Anti-CTLA-4 mAb ligation assay; cytokine ELISA; flow cytometry cell cycle analysis; exogenous IL-2 rescue experiment The Journal of experimental medicine High 8676075
1993 CTLA-4 expression is induced on activated T cells (not detectable on resting T cells), is regulated by PKC-dependent signaling, and exists as a ~41-43 kDa protein that migrates primarily as a monomer at the cell surface rather than as a disulfide-bonded homodimer or CD28 heterodimer. Anti-CTLA-4 rabbit antiserum; [35S]methionine metabolic labeling; 125I surface labeling; SDS-PAGE; Northern blot; PKC inhibitor experiments Journal of immunology Medium 8397258
1993 B7-2 (a second ligand distinct from B7-1/CD80) can bind CTLA-4 and provide costimulatory signals; CTLA4-Ig fusion protein blocks both B7 and B7-2 interactions, indicating CTLA-4 engages two distinct B7-family ligands on antigen-presenting cells. CTLA4-Ig blocking experiments; anti-B7 mAb blocking; T cell proliferation assays; B cell stimulation with LPS Proceedings of the National Academy of Sciences of the United States of America High 7504292
1996 CTLA-4 expression is transcriptionally induced upon T cell activation; 335 bp of upstream CTLA-4 sequence are sufficient to control inducibility; both positive and negative response elements modulate transcriptional regulation; expression is T cell-specific. Nuclear run-off assay; Northern blot; reporter gene analysis; non-T cell Northern blot analysis Journal of immunology Medium 8666782
1996 In vivo blockade of CTLA-4 with antibodies results in rejection of preestablished tumors and induces immunity to secondary tumor exposure, demonstrating CTLA-4 negatively regulates antitumor immune responses in vivo. In vivo anti-CTLA-4 antibody administration in tumor-bearing mice; rechallenge with tumor cells Science High 8596936
2002 CTLA-4 regulates cell cycle progression during primary immune responses: in the absence of CTLA-4, T cells show increased cycling in S and G2/M phases, increased IL-2 production, and delayed re-expression of the cell cycle inhibitor p27kip1, indicating CTLA-4 enforces the G1-to-S phase transition checkpoint. CTLA-4 knockout vs wild-type T cell comparison; flow cytometry cell cycle analysis; cyclin/CDK protein analysis; IL-2 mRNA and protein assays European journal of immunology High 11807776
2008 Treg-specific CTLA-4 deficiency results in spontaneous systemic lymphoproliferation, fatal autoimmune disease, and impairs Treg-mediated downregulation of CD80 and CD86 expression on dendritic cells, establishing that CTLA-4 on Tregs suppresses immune responses by controlling APC costimulatory ligand expression. Conditional CTLA-4 knockout in Foxp3+ Tregs; in vivo and in vitro Treg suppression assays; flow cytometry for CD80/CD86 on DCs Science High 18845758
2008 CTLA-4 directly inhibits osteoclast formation dose-dependently in vitro (in the absence of T cells), inhibiting both RANKL- and TNF-mediated osteoclastogenesis, and also inhibits TNF-induced osteoclast formation in a non-T cell-dependent arthritis model in vivo. In vitro osteoclastogenesis assay with CTLA-4 protein; TNF-induced arthritis mouse model; histological analysis of bone erosion Annals of the rheumatic diseases Medium 18203760
2008 CTLA-4 surface expression is primarily regulated by restricted trafficking: the majority of CTLA-4 is intracellular, and several signaling molecules including TRIM, PLD, ARF-1, and TIRC7 are involved in transport of CTLA-4 to the cell surface; minor changes in surface expression levels have major effects on T cell activation outcome. Subcellular fractionation; co-immunoprecipitation with TRIM, PLD, ARF-1; flow cytometry surface expression analysis Trends in immunology Medium 18468488
2009 CTLA-4 inhibitory signaling in Treg cells controls T cell proliferation and confers resistance against activation-induced cell death (AICD) mediated by CD95/CD95L-caspase pathway; blockade of CTLA-4 signaling in Tregs reduces their suppressive capacity. Transfer of CTLA-4-competent Tregs into CTLA-4-deficient mice significantly prolongs their survival. In vitro CTLA-4 blockade on Treg cells; cell cycle analysis; apoptosis assay; caspase activation assay; adoptive transfer into CTLA-4-deficient mice Arthritis and rheumatism Medium 19116935
2010 CTLA-4 inhibits T cell function by activating the ubiquitin ligase Itch: CTLA-4-mediated signaling leads to dephosphorylation/activation of Itch and enhanced ubiquitination of the Itch target molecule JunB; Itch knockdown abolishes CTLA-4-mediated inhibition of IFN-γ and IL-4 mRNA accumulation. Itch knockdown (siRNA/shRNA); phosphorylation assay; ubiquitination assay; cytokine mRNA analysis; comparison of CTLA-4- and Itch-deficient mice phenotypes Molecular immunology Medium 20417562
2002 CTLA-4 is constitutively expressed by human monocytes (surface ~3%, intracellular ~20%), and ligation of CTLA-4 in monocytes suppresses proliferation, upregulation of CD86/CD54/HLA-DR/HLA-DQ, and inhibits AP-1 and NF-κB activation. Flow cytometry; cDNA sequencing; IFN-γ/PMA stimulation; anti-CTLA-4 mAb ligation; AP-1/NF-κB reporter assay in U937 cells Scandinavian journal of immunology Medium 11841692
2002 cAMP and calcium ionophore (ionomycin) independently induce upregulation of CD152 (CTLA-4) in resting human CD4+ T cells; cAMP-induced upregulation is cyclosporin A-resistant whereas ionomycin-induced upregulation is cyclosporin A-sensitive (calcineurin-dependent); the upregulated CTLA-4 is functional and prevents NF-κB activation upon anti-CD3/CD28 stimulation. Flow cytometry; RT-PCR; cyclosporin A inhibition; NF-κB reporter assay; anti-CD3/CD28 stimulation Journal of immunology Medium 12444128
2014 CTLA-4 surface expression is regulated by multiple trafficking mechanisms involving TRIM and LAX (immune cell-specific adapters), Rab8 GTPase, ARF-1, phospholipase D, and the AP1/2 clathrin adaptor complex, which collectively control CTLA-4 transport to the cell surface and its residency. Co-immunoprecipitation; dominant-negative/constitutively active GTPase expression; surface expression assays; internalization assays Frontiers in immunology Medium 25538704
2021 CTLA-4 recycling to the cell surface is regulated by LRBA and Rab11: CTLA-4 distributes across Rab5, Rab7, and Rab11 compartments; dominant-negative Rab5 increases surface CTLA-4; constitutively active Rab11 increases and dominant-negative Rab11 decreases surface CTLA-4; LRBA deficiency impairs CTLA-4 recycling and increases its degradation, and LRBA acts upstream of Rab11. Dominant-negative and constitutively active Rab GTPase expression; LRBA knockdown/knockout; flow cytometry surface expression; colocalization microscopy; degradation assays in HeLa and Jurkat cells Immunology High 33960403
2019 Ipilimumab and TremeIgG1 (irAE-prone antibodies) rapidly direct cell surface CTLA-4 to lysosomal degradation, whereas non-irAE-prone antibodies allow CTLA-4 to recycle to the cell surface via the LRBA-dependent mechanism. Disrupting CTLA-4 recycling (via LRBA knockout) causes robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity. Introducing pH-sensitive tyrosine-to-histidine mutations in TremeIgG1 prevents lysosomal CTLA-4 downregulation and attenuates irAE while improving antitumor efficacy. LRBA knockout cells; antibody endocytosis and recycling assays; lysosomal tracking; pH-sensitive antibody mutagenesis; in vivo tumor models; intratumor Treg depletion assays Cell research High 31267017
2021 CTLA-4 blockade destabilizes tumor-infiltrating Treg cells toward IFNγ- and TNF-producing cells in glycolysis-defective tumors; this effect depends on Treg cell glycolysis and CD28 signaling, establishing that glucose availability in the tumor microenvironment gates the effect of CTLA-4 blockade on Treg stability. Glycolysis-defective tumor mouse models; anti-CTLA-4 antibody treatment; metabolic analysis; in vitro mimicry of glycolytic tumor microenvironment; flow cytometry for Treg phenotype; CD28 blocking experiments Nature High 33588426
2022 CTLA-4 performs transendocytosis of both CD80 and CD86, but the fates differ: in the presence of CD80, CTLA-4 remains ligand-bound, is ubiquitylated, and is trafficked to late endosomes/lysosomes for degradation; in the presence of CD86, CTLA-4 detaches in a pH-dependent manner and recycles to the cell surface for further transendocytosis. Clinically relevant autoimmune-associated mutations selectively disrupt CD86 transendocytosis by affecting either CTLA-4 recycling or CD86 binding, identifying CD86 as the key target for CTLA-4 immune regulation. Transendocytosis assays; pH-dependent dissociation assays; ubiquitylation assays; endosomal trafficking/colocalization studies; functional analysis of clinical CTLA-4 mutations Nature immunology High 35999394
1999 Interaction of CTLA-4 with CD80 or CD86 on human T cells inhibits T cell activation (cytokine production, proliferation, and cytotoxic responses) in polyclonal and alloantigen-specific assays; CTLA-4-mediated inhibition operates independently of CD28 occupancy. Anti-CTLA-4 mAb blocking (soluble and Fab fragments); T cell proliferation assays; cytokine ELISA; cytotoxicity assays Immunology Medium 10583602
2000 Selective CTLA-4 ligation using a membrane-bound single-chain antibody (scFv) on artificial APCs reduces T cell proliferation and IL-2 production and inhibits tyrosine phosphorylation of proximal TCR signaling components; this inhibitory effect requires coexpression of TCR and CTLA-4 ligands on the same surface, demonstrating that CTLA-4 modifies the proximal TCR signal in cis. Surface-linked scFv to CTLA-4; co-expression of anti-CD3ε and anti-CD28 scFvs; proliferation assays; IL-2 ELISA; tyrosine phosphorylation assay; TCR transgenic T cells Journal of immunology Medium 10779742
2021 CTLA-4 expression on B-1a B cells (not only T cells) is critical for immune tolerance: selective deletion of CTLA-4 from B cells causes spontaneous autoantibodies, T follicular helper cell expansion, germinal center formation, and autoimmune pathology; CTLA-4-deficient B-1a cells upregulate epigenetic/transcriptional activation, show increased self-replenishment, internalize surface IgM, differentiate into APCs, and upon transfer induce germinal centers in normal recipients. B cell-specific CTLA-4 conditional knockout; flow cytometry; autoantibody detection; adoptive transfer; transcriptomic/epigenomic analysis Nature communications High 33483505
2023 The alternatively spliced soluble CTLA-4 isoform (sCTLA-4) suppresses CD8+ T cells in vitro and accelerates tumor growth and metastasis in vivo; sCTLA-4 expression by tumor cells restrains intratumoral CD8+ T cells in a non-cytotoxic state; isoform-specific anti-sCTLA-4 antibody blockade reverses this restraint and enhances CD8+ T cell cytolytic potential. In vitro CD8+ T cell suppression assay; syngeneic mouse tumor growth and metastasis models; isoform-specific antibody blockade; flow cytometry immune infiltrate analysis Molecular therapy Medium 38053333
2014 Soluble CTLA-4 (sCTLA-4) is generated by alternatively spliced mRNA lacking the transmembrane-encoding exon 3; the sCTLA-4 protein is secreted at low levels by activated primary human CD4+ T cells; transmembrane CTLA-4 (Tm-CTLA-4) is unexpectedly associated with microvesicles produced by activated T cells. Novel isoform-specific mAbs and polyclonal Abs; ELISA; flow cytometry; microvesicle isolation; activated CD4+ T cell cultures Journal of immunology Medium 24928993
2018 CTLA-4 expressed on mesenchymal stem/stromal cells (MSCs) mediates their immunosuppressive function; under hypoxic conditions, the secreted isoform (sCTLA-4) is the most abundant; immunosuppression by MSCs is mediated mainly by sCTLA-4 secretion. CTLA-4 isoform expression analysis; functional immunosuppression assays with CTLA-4 blockade; hypoxia experiments International journal of molecular sciences Low 30087255
2023 Fusion of CTLA-4 cytoplasmic tail (CCT) to CAR constructs progressively lowers CAR surface expression via constant endocytosis, recycling, and degradation; this reduces CAR-mediated trogocytosis and tumor antigen loss, enhances CAR-T persistence and central memory phenotype, and improves antitumor efficacy in a relapsed leukemia model. CAR-T cell engineering with monomeric/duplex/triplex CCT fusions; surface expression assays; trogocytosis assay; in vivo leukemia model; scRNA-seq; flow cytometry Nature immunology High 37500885

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Enhancement of antitumor immunity by CTLA-4 blockade. Science (New York, N.Y.) 3032 8596936
2015 Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science (New York, N.Y.) 2751 26541610
2008 CTLA-4 control over Foxp3+ regulatory T cell function. Science (New York, N.Y.) 2380 18845758
2015 Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science (New York, N.Y.) 2284 26359337
2016 CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. American journal of clinical oncology 1848 26558876
1995 CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. The Journal of experimental medicine 1749 7543139
2017 CTLA-4: a moving target in immunotherapy. Blood 957 29118008
2019 Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Molecular cancer 934 31690319
2001 Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annual review of immunology 811 11244036
2018 Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nature medicine 763 30397353
2019 Combination of CTLA-4 and PD-1 blockers for treatment of cancer. Journal of experimental & clinical cancer research : CR 724 31196207
2002 CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nature immunology 705 12087419
2009 CD28 and CTLA-4 coreceptor expression and signal transduction. Immunological reviews 687 19426212
2001 T-cell regulation by CD28 and CTLA-4. Nature reviews. Immunology 687 11905831
1996 CTLA-4 ligation blocks CD28-dependent T cell activation. The Journal of experimental medicine 638 8676075
1992 Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. The Journal of experimental medicine 546 1334116
2006 A molecular perspective of CTLA-4 function. Annual review of immunology 425 16551244
2013 Treg and CTLA-4: two intertwining pathways to immune tolerance. Journal of autoimmunity 336 23849743
2000 CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity? Genes and immunity 331 11196709
2021 CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature 325 33588426
2013 At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. Journal of leukocyte biology 289 23625198
2015 Confusing signals: recent progress in CTLA-4 biology. Trends in immunology 279 25582039
1993 Characterization of CTLA-4 structure and expression on human T cells. Journal of immunology (Baltimore, Md. : 1950) 264 8397258
1993 Expression and functional significance of an additional ligand for CTLA-4. Proceedings of the National Academy of Sciences of the United States of America 257 7504292
2020 CTLA-4: From mechanism to autoimmune therapy. International immunopharmacology 239 32007707
2021 CTLA-4 in Regulatory T Cells for Cancer Immunotherapy. Cancers 224 33809974
1997 Is CTLA-4 a master switch for peripheral T cell tolerance? Journal of immunology (Baltimore, Md. : 1950) 198 9036940
2020 Molecular and Cellular Functions of CTLA-4. Advances in experimental medicine and biology 188 32185705
2015 CTLA-4 and PD-1 Pathway Blockade: Combinations in the Clinic. Frontiers in oncology 187 25642417
1996 Regulation of CTLA-4 expression during T cell activation. Journal of immunology (Baltimore, Md. : 1950) 179 8666782
2022 Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation. Nature immunology 178 35999394
2003 Multivalent RNA aptamers that inhibit CTLA-4 and enhance tumor immunity. Cancer research 166 14612549
2023 Current understanding of CTLA-4: from mechanism to autoimmune diseases. Frontiers in immunology 165 37497212
2008 CTLA-4 directly inhibits osteoclast formation. Annals of the rheumatic diseases 160 18203760
2011 Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends in immunology 152 21723783
1999 CTLA-4 and T cell activation. Current opinion in immunology 148 10375557
2008 CTLA-4: a key regulatory point in the control of autoimmune disease. Immunological reviews 143 18613834
2018 Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade. Cell 140 29656892
2000 CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. Journal of hepatology 140 10782900
2018 Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 138 29794465
2019 What did we learn from CTLA-4 insufficiency on the human immune system? Immunological reviews 134 30565239
2008 CTLA-4 trafficking and surface expression. Trends in immunology 133 18468488
2000 NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans. Diabetes 130 11016460
2017 CTLA-4, an Essential Immune-Checkpoint for T-Cell Activation. Current topics in microbiology and immunology 125 28900679
2001 CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production. The Journal of clinical endocrinology and metabolism 124 11297604
2013 CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance. Autoimmunity reviews 113 23851140
1999 The CTLA-4 gene is associated with multiple sclerosis. Journal of neuroimmunology 112 10408973
2003 CTLA-4 and its role in autoimmune thyroid disease. Journal of molecular endocrinology 111 12914522
2021 Therapeutic options for CTLA-4 insufficiency. The Journal of allergy and clinical immunology 107 34111452
2015 CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Cancer medicine 103 25619164
2014 Understanding the CD28/CTLA-4 (CD152) pathway and its implications for costimulatory blockade. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 103 25098238
2002 CTLA-4 regulates cell cycle progression during a primary immune response. European journal of immunology 101 11807776
2017 Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clinical and experimental immunology 99 28600865
2020 CTLA-4 correlates with immune and clinical characteristics of glioma. Cancer cell international 98 31911758
2005 Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia. Leukemia 92 16094420
2019 Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell research 90 31267017
2000 Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33. Diabetes 89 10868973
2004 The emerging role of the CTLA-4 gene in autoimmune endocrinopathies. European journal of endocrinology 87 15132716
2010 Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 86 21083648
2009 CTLA-4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice. Arthritis and rheumatism 85 19116935
1999 Interaction of CTLA-4 (CD152) with CD80 or CD86 inhibits human T-cell activation. Immunology 85 10583602
2004 Unravelling the genetic complexity of autoimmune thyroid disease: HLA, CTLA-4 and beyond. Clinical and experimental immunology 78 15030506
2002 Expression of CTLA-4 by human monocytes. Scandinavian journal of immunology 77 11841692
2008 Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with ipilimumab (MDX-010). The oncologist 76 19001147
2021 CTLA-4 expression by B-1a B cells is essential for immune tolerance. Nature communications 69 33483505
2005 HLA , CTLA-4 and PTPN22 : the shared genetic master-key to autoimmunity? Expert reviews in molecular medicine 69 16229750
2019 CTLA-4 (CD152): A versatile receptor for immune-based therapy. Seminars in immunology 65 31604536
2006 Association of CTLA-4 gene polymorphism with oral squamous cell carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 63 16393254
2003 CTLA-4 and tolerance: the biochemical point of view. Immunologic research 57 14713717
1999 Enhanced expression of CTLA-4 (CD152) on CD4+ T cells in HIV infection. Clinical and experimental immunology 57 10193417
2010 The soluble CTLA-4 receptor and its role in autoimmune diseases: an update. Auto- immunity highlights 56 26000110
2014 Diverse mechanisms regulate the surface expression of immunotherapeutic target ctla-4. Frontiers in immunology 55 25538704
2017 EFIS Lecture: Understanding the CTLA-4 checkpoint in the maintenance of immune homeostasis. Immunology letters 51 28216262
2017 A CTLA-4 Antagonizing DNA Aptamer with Antitumor Effect. Molecular therapy. Nucleic acids 51 28918052
1999 The role of cytokines, CTLA-4 and costimulation in transplant tolerance and rejection. Current opinion in immunology 51 10508707
2017 Lessons from CTLA-4 deficiency and checkpoint inhibition. Current opinion in immunology 50 28806575
2000 Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152). Journal of immunology (Baltimore, Md. : 1950) 48 10779742
2023 Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity. Molecular therapy : the journal of the American Society of Gene Therapy 45 38053333
2008 CTLA-4 blockade with monoclonal antibodies in patients with metastatic cancer: surgical issues. Annals of surgical oncology 44 18716842
2023 CTLA-4 tail fusion enhances CAR-T antitumor immunity. Nature immunology 42 37500885
2010 ctla-4 gene variations may influence cervical cancer susceptibility. Gynecologic oncology 41 20615526
2021 Regulation of CTLA-4 recycling by LRBA and Rab11. Immunology 40 33960403
2015 Emerging targets in cancer immunotherapy: beyond CTLA-4 and PD-1. Immunotherapy 40 26567614
2021 Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation. Blood 39 33720354
2005 The soluble CTLA-4 receptor: a new marker in autoimmune diseases. Archivum immunologiae et therapiae experimentalis 39 16088318
2002 Cyclic adenosine 5'-monophosphate and calcium induce CD152 (CTLA-4) up-regulation in resting CD4+ T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 39 12444128
2016 CTLA-4 Limits Anti-CD20-Mediated Tumor Regression. Clinical cancer research : an official journal of the American Association for Cancer Research 38 27354469
2016 CTLA-4 blockade in the treatment of rheumatoid arthritis: an update. Expert review of clinical immunology 37 26679631
2018 CTLA-4 Mediates Inhibitory Function of Mesenchymal Stem/Stromal Cells. International journal of molecular sciences 36 30087255
1992 CTLA-4 and CD28: similar proteins, neighbouring genes. International journal of cancer. Supplement = Journal international du cancer. Supplement 36 1330947
2013 Pruritus to anticancer agents targeting the EGFR, BRAF, and CTLA-4. Dermatologic therapy 35 23551370
2014 Investigation of soluble and transmembrane CTLA-4 isoforms in serum and microvesicles. Journal of immunology (Baltimore, Md. : 1950) 34 24928993
2010 CTLA-4 (CD152) inhibits T cell function by activating the ubiquitin ligase Itch. Molecular immunology 33 20417562
2021 CTLA-4 Expression and Its Clinical Significance in Breast Cancer. Archivum immunologiae et therapiae experimentalis 31 34148159
2020 FoxP3, CTLA-4, and IDO in Canine Melanocytic Tumors. Veterinary pathology 31 33021155
2018 PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity. The Journal of clinical endocrinology and metabolism 31 29409002
2017 Regulatory T cells and CTLA-4 in idiopathic nephrotic syndrome. Pediatrics international : official journal of the Japan Pediatric Society 31 28544686
2023 Bispecific antibodies targeting CTLA-4: game-changer troopers in cancer immunotherapy. Frontiers in immunology 30 37441075
2001 Expression and functional significance of CTLA-4, a negative regulator of T cell activation. Archivum immunologiae et therapiae experimentalis 30 11266089
2014 Braking bad: novel mechanisms of CTLA-4 inhibition of T cell responses. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 29 25387592

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