Affinage

ICOS

Inducible T-cell costimulator · UniProt Q9Y6W8

Length
199 aa
Mass
22.6 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ICOS is an activation-induced T-cell co-stimulatory receptor that, through its exclusive ligand ICOSL (B7RP-1), drives germinal centre formation, T follicular helper (Tfh) cell differentiation and maintenance, regulatory T-cell IL-10 production, iNKT cell activation, and CD8+ tissue-resident memory T-cell establishment (PMID:9930702, PMID:11343123, PMID:25692700, PMID:34932944, PMID:18390727, PMID:22815292). Structurally, ICOS binds ICOSL via a central FDPPPF motif and CC' loop with direct participation of an N110-linked glycan, and its transmembrane domain recruits Lck, which is required for p85/PI3K recruitment to the ICOS cytoplasmic tail; downstream PI3K-AKT signaling inactivates FOXO1 to suppress Klf2, thereby establishing the Tfh homing receptor program, while a membrane-proximal cytoplasmic motif potentiates PLCγ1-dependent calcium flux and RhoA/Cdc42-mediated actin remodeling (PMID:33033255, PMID:30523347, PMID:12594849, PMID:25692700, PMID:25646266, PMID:27693916). ICOS expression is transcriptionally controlled by Fyn–calcineurin–NFATc2 and MEK–ERK pathways, and post-transcriptionally repressed by Roquin/NUFIP2-mediated decay targeting stem-loops in the ICOS 3′-UTR (PMID:16880206, PMID:29352114). Homozygous ICOS deletion in humans causes common variable immunodeficiency characterized by defective B-cell class-switching and memory B-cell generation (PMID:12577056).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    Identification of ICOS as a novel activation-induced T-cell co-stimulatory receptor established that the CD28 superfamily contained a second, non-redundant co-stimulatory pathway with distinct cytokine output (IL-10 superinduction, no IL-2 upregulation).

    Evidence Molecular cloning, flow cytometry, functional co-stimulation assays, and immunohistochemistry of human tonsil T cells

    PMID:9930702

    Open questions at the time
    • Ligand identity unknown at time of discovery
    • Signaling pathway downstream of ICOS uncharacterized
    • Tissue distribution beyond tonsil not fully mapped
  2. 2000 High

    Discovery of B7RP-1/ICOSL as the exclusive ICOS ligand, and demonstration that ICOS–ICOSL and CD28–B7 systems do not cross-react, defined two parallel but independent co-stimulatory axes in adaptive immunity.

    Evidence Receptor–ligand binding assays and fusion-protein co-stimulation in murine system; additional biochemical characterization of human ICOS homodimer

    PMID:10617205 PMID:11169414

    Open questions at the time
    • Structural basis of ligand specificity unknown
    • ICOS–ICOSL affinity and kinetics not quantified
  3. 2001 High

    ICOS knockout mice revealed that ICOS is essential in vivo for germinal centre formation, Ig class switching, and T-dependent B-cell responses, while CTLA-4 was shown to antagonize ICOS-mediated cytokine production, establishing a co-stimulatory/co-inhibitory regulatory circuit.

    Evidence ICOS-deficient mouse phenotyping; anti-CTLA-4/anti-ICOS bead stimulation and IL-2 rescue experiments

    PMID:11290772 PMID:11343123

    Open questions at the time
    • Downstream signaling intermediates not identified
    • Mechanism of CTLA-4 suppression of ICOS expression unresolved
  4. 2003 High

    Human ICOS deficiency was linked to common variable immunodeficiency, and ICOS signaling was shown to proceed through PI3K recruitment and MAP kinase activation, connecting receptor engagement to cytokine gene regulation.

    Evidence Homozygous ICOS deletion in patients with immunophenotyping; ICOS cross-linking with PI3K inhibitors and kinase assays in Th2 clones

    PMID:12577056 PMID:12594849

    Open questions at the time
    • PI3K-binding motif on ICOS not mapped
    • Transcription factors downstream of PI3K not identified
  5. 2006 High

    Defining the Fyn–calcineurin–NFATc2 and MEK–ERK transcriptional circuits controlling ICOS promoter activity explained how TCR signal strength and co-stimulation regulate ICOS expression levels.

    Evidence ChIP of NFATc2 on icos promoter, luciferase reporters, Fyn−/− T cells, chemical inhibitors

    PMID:16880206

    Open questions at the time
    • Chromatin accessibility and epigenetic regulation of icos locus not addressed
    • Post-transcriptional regulation not yet characterized
  6. 2008 High

    Epistasis experiments placed ICOS upstream of CD40 and LTβR in germinal centre network formation, and demonstrated ICOS is required for iNKT cell homeostasis and effector function, broadening ICOS function beyond conventional T cells.

    Evidence ICOS−/− mice with agonistic anti-CD40 rescue; ICOS−/− and ICOSL−/− mice with α-GalCer challenge and adoptive iNKT transfer

    PMID:18250437 PMID:18390727

    Open questions at the time
    • Molecular mechanism linking ICOS to LTαβ induction on B cells not defined
    • iNKT-intrinsic vs. extrinsic ICOS requirement not fully separated
  7. 2013 High

    Two-photon imaging showed ICOS drives T-cell pseudopod formation and persistent migration at the T–B border via bystander B-cell ICOSL, explaining how ICOS positions T cells for follicular entry independently of Bcl6; separately, ICOS was shown essential for Treg IL-10 production and suppressive function.

    Evidence Intravital two-photon microscopy with ICOS-deficient and ICOSL conditional-KO mice; ICOS−/− Treg transfer in airway tolerance and helminth models

    PMID:22815292 PMID:23319295 PMID:23619696

    Open questions at the time
    • Cytoskeletal effectors downstream of ICOS mediating pseudopod formation not identified
    • Whether ICOS-dependent Treg IL-10 operates through PI3K–FOXO1 untested
  8. 2015 High

    Genetic epistasis established that ICOS signals through PI3K to inactivate FOXO1, which in turn represses Klf2; Klf2 directly controls Tfh homing receptors (CXCR5, CCR7, PSGL1, S1PR1), providing a complete transcriptional pathway from receptor to cell positioning.

    Evidence Foxo1 conditional KO and nuclear-localization KI mice crossed to ICOS−/−; Klf2 ChIP on Tfh target promoters with ICOS blockade

    PMID:25646266 PMID:25692700

    Open questions at the time
    • Whether additional transcription factors act in parallel with FOXO1 downstream of ICOS not tested
    • Kinetics of FOXO1 inactivation upon ICOS ligation not measured
  9. 2016 High

    A membrane-proximal cytoplasmic motif of ICOS was shown to potentiate calcium signaling via PLCγ1 activation and RhoA/Cdc42-dependent actin remodeling, revealing a PI3K-independent arm of ICOS signaling.

    Evidence ICOS cytoplasmic domain mutagenesis knock-in mice with calcium flux, PLCγ1 phosphorylation, and small GTPase activation assays

    PMID:27693916

    Open questions at the time
    • Identity of the adaptor linking the proximal motif to RhoA/Cdc42 unknown
    • Relative contribution of calcium vs. PI3K arm to individual T-cell fates not quantified
  10. 2018 High

    The ICOS transmembrane domain was identified as the site of Lck association, which is prerequisite for p85/PI3K recruitment and downstream Tfh/GC responses, resolving how ICOS activates PI3K despite lacking a classical ITAM; simultaneously, Roquin/NUFIP2-dependent mRNA decay targeting dual stem-loops in the ICOS 3′-UTR was established as the major post-transcriptional brake on ICOS levels, and Peli1 was identified as a transcriptional negative regulator via c-Rel.

    Evidence Domain-swap constructs with co-IP and in vivo Tfh/GC analysis; genome-wide RNAi screen with 3′-UTR mutagenesis; Peli1-KO mice with PI3K-AKT and Klf2 readouts

    PMID:29352114 PMID:30523347 PMID:33707688

    Open questions at the time
    • Structural basis of TMD–Lck interaction unresolved
    • How Roquin selects ICOS mRNA over other targets not fully elucidated
    • Whether Peli1 directly ubiquitinates c-Rel to limit ICOS transcription not shown
  11. 2020 High

    The crystal structure of the ICOS–ICOSL complex at 3.3 Å revealed that the FDPPPF motif and CC' loop (with N110 glycan) mediate ligand specificity via a binding orientation distinct from CD28–B7, providing a structural rationale for the non-cross-reactivity of these pathways.

    Evidence X-ray crystallography at 3.3 Å with binding-assay validation

    PMID:33033255

    Open questions at the time
    • No structure of full-length ICOS including TMD and cytoplasmic domain
    • Dynamics of ICOS dimerization and its role in signaling complex assembly not characterized
  12. 2021 High

    ICOS–PI3K signaling in the tissue effector phase was shown to be required for establishment of CD8+ tissue-resident memory T cells independently of priming, expanding the functional repertoire of ICOS beyond CD4+ T-cell help; in a distinct context, ICOS–PI3K signaling was found to limit visceral adipose tissue Treg accumulation, revealing context-dependent effects on Treg biology.

    Evidence ICOS−/− and IcosYF/YF KI mice with adoptive transfer and temporal ICOSL blockade for Trm; same genetic models on high-fat diet for VAT-Treg analysis

    PMID:33881452 PMID:34932944

    Open questions at the time
    • Downstream effectors of PI3K that distinguish Trm establishment from Tfh programming not identified
    • Whether ICOS limits VAT-Tregs through FOXO1–Klf2 axis specifically not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of TMD–Lck association, how ICOS signal strength is integrated across the PI3K and calcium arms to specify distinct T-cell fates (Tfh vs. Treg vs. Trm), and whether ICOS-dependent metabolic reprogramming (glycolysis) is a general feature of its signaling or context-restricted.
  • No structure of ICOS TMD–Lck interface
  • Quantitative signaling model integrating PI3K and PLCγ1 arms absent
  • Metabolic consequences of ICOS signaling tested only in CIA model

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 4
Partners
FOXO1ICOSLLCKNFATC2NUFIP2PELI1PIK3R1RC3H1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 ICOS is a homodimeric T-cell-specific cell-surface protein (Mr 55K-60K) that is de novo induced on T-cell surfaces upon activation (unlike constitutively expressed CD28), co-stimulates T-cell proliferation, lymphokine secretion, and B-cell help, superinduces IL-10 but does not upregulate IL-2, and is highly expressed on tonsillar germinal-centre T cells. Molecular cloning, flow cytometry, functional co-stimulation assays, immunohistochemistry Nature High 9930702
1999 ICOS (murine homologue) binds specifically to B7-related protein-1 (B7RP-1/ICOSL), a B7-family ligand expressed on B cells and macrophages; this receptor-ligand pair does not cross-interact with CD28, B7-1, or B7-2, defining a distinct co-stimulatory pathway. Receptor-ligand binding assays, fusion-protein co-stimulation, transgenic mouse overexpression Nature High 10617205
2001 ICOS is essential in vivo for T-cell-dependent B-cell responses: ICOS-deficient mice show severely impaired germinal centre formation, defective immunoglobulin class switching (including IgE), reduced IL-4 production by primed T cells, and deficient T-B cell interactions. Gene-targeted ICOS-knockout mouse generation and phenotypic characterization, in vitro restimulation assays Nature High 11343123
2000 ICOS expression is upregulated by CD28 co-stimulation (CD80/CD86-dependent) and promotes CD4+ T-cell proliferation and production of IFN-γ, IL-4, and IL-10 but not IL-2; blocking ICOS:B7h interaction shifts differentiation away from Th2 toward Th1. Anti-mouse ICOS mAbs and ICOS-Ig fusion protein blockade, bead-based co-stimulation assays, TCR-transgenic T-cell differentiation Journal of immunology High 11046032
2003 Homozygous deletion of the ICOS gene in humans causes adult-onset common variable immunodeficiency with reduced naive, switched, and memory B cells, demonstrating ICOS is critical for T-cell help for late B-cell differentiation, class-switching, and memory B-cell generation. Genetic analysis (homozygous deletion), immunophenotyping of patient T and B cells Nature immunology High 12577056
2003 ICOS signals through PI3K (recruitment to ICOS cytoplasmic domain upon cross-linking) and enhances TCR-proximal signals including ZAP-70, zeta, Vav phosphorylation and ERK, JNK, and p38 MAP kinase activation; PI3K activity is required for ERK/JNK activation and IL-4/IL-10 secretion. ICOS cross-linking, kinase activity assays, PI3K inhibitors, phosphorylation western blots in Th2 clones European journal of immunology High 12594849
2000 Human ICOS is a 55-60 kDa homodimer with N-glycosylated subunits of 27 and 29 kDa; it requires PMA plus ionomycin for full induction, is sensitive to cyclosporin A, does not bind B7-1 or B7-2, and maps to chromosome 2q33-34. CD28/B7 but not CD40L/CD40 pathway is critically involved in ICOS induction by APCs. ICOS co-stimulation prevents apoptosis of pre-activated T cells and superinduces IL-10. Biochemical characterization, flow cytometry, cytokine assays, chromosomal mapping European journal of immunology High 11169414
2001 CTLA-4 ligation blocks ICOS co-stimulation both indirectly (by preventing ICOS surface expression on resting cells) and directly (by blocking ICOS-mediated IL-4, IL-10, IL-13 induction on pre-activated cells); exogenous IL-2 overcomes both mechanisms and is required for sustained ICOS-costimulated T-cell growth. Anti-CD3/anti-ICOS/anti-CTLA-4 bead stimulation, cytokine ELISA, IL-2 neutralization and addition experiments Journal of immunology High 11290772
2006 ICOS expression is transcriptionally controlled by the Fyn-calcineurin-NFATc2 axis and a separate MEK2-ERK1/2 pathway; NFATc2 binds the icos promoter in vivo and this binding is reduced in Fyn-/- T cells; ectopic NFATc2 or constitutively active MEK2 transactivates a 288-bp core icos promoter region. Chemical inhibitors (PP2, U0126, CsA, FK506), luciferase reporter assays, ChIP, Fyn-/- mice Journal of biological chemistry High 16880206
2013 ICOS directly drives follicular recruitment of activated T-helper cells by promoting pseudopod formation and persistent T-cell migration at the T-zone/B-follicle border; this requires ICOSL expression by follicular bystander B cells and is independent of ICOSL on dendritic cells or cognate B cells, and does not require Bcl6 as an intermediate. Two-photon intravital microscopy (dynamic imaging), ICOS-deficient and ICOSL conditional-KO mice, Bcl6 genetic analysis Nature High 23619696
2015 ICOS co-stimulation signals via PI3K to inactivate the transcription factor FOXO1, promoting Tfh cell differentiation; Foxo1 deletion rescues Tfh generation in ICOS-deficient conditions, while enforced nuclear FOXO1 blocks Tfh development even with ICOS overexpression; final GC-Tfh differentiation requires FOXO1 activity. Foxo1 conditional KO and nuclear-localization knock-in mice, ICOS-deficient mice, flow cytometry, gene expression analysis Immunity High 25692700
2015 ICOS (but not CD28) co-stimulation is exclusively required for maintaining the Tfh phenotype by downregulating the transcription factor Klf2 via Foxo1; Klf2 directly binds to Cxcr5, Ccr7, Psgl-1, and S1pr1 promoters, and low Klf2 levels maintain the Tfh homing receptor pattern and follicular localization. ICOS blockade in vivo, Klf2 ChIP, conditional KO mice, gene expression and flow cytometry Journal of experimental medicine High 25646266
2018 The ICOS transmembrane domain (TMD) is required for association with the tyrosine kinase Lck, and this TMD-Lck association is necessary for p85 (PI3K regulatory subunit) recruitment to ICOS and downstream PI3K activation, as well as for costimulation of calcium mobilization; the ICOS cytoplasmic domain alone is insufficient for these functions. TMD-replaced ICOS fails to support Tfh development or GC formation in vivo. ICOS domain-swap constructs, co-immunoprecipitation, calcium flux assays, Lck co-association, in vivo Tfh/GC analysis Cellular & molecular immunology High 30523347
2016 ICOS potentiates TCR-induced calcium flux by enhancing PLCγ1 activation and actin remodeling (via RhoA and Cdc42 activation); a membrane-proximal cytoplasmic motif is essential for this calcium-signaling function; interruption of actin dynamics impairs calcium flux even with activated PLCγ1. ICOS cytoplasmic domain mutagenesis knock-in mice, calcium flux assays, PLCγ1 phosphorylation assays, small GTPase activation assays, actin inhibitors Molecular immunology High 27693916
2018 Peli1 (an E3 ubiquitin ligase) negatively regulates ICOS expression by limiting c-Rel-mediated ICOS transcription; increased ICOS in Peli1-KO T cells enhances PI3K-AKT signaling, suppresses Klf2, and promotes Tfh differentiation. Mixed bone marrow chimeras, Peli1-KO mice, c-Rel analysis, PI3K-AKT signaling assays, Klf2 reconstitution Cellular & molecular immunology High 33707688
2020 Crystal structure of the ICOS/ICOS-L complex at 3.3 Å resolution reveals that a central FDPPPF motif and CC' loop residues of ICOS mediate specificity of ICOS-L binding with a distinct receptor orientation compared to CD28/B7; the N110 N-linked glycan of ICOS participates directly in ICOS-L binding. X-ray crystallography (3.3 Å), binding assays, structural comparison Nature communications High 33033255
2018 Binding of NUFIP2 to Roquin-1/2 promotes recognition of ICOS mRNA; post-transcriptional repression of human ICOS by Roquin requires two neighboring non-canonical stem-loops in the ICOS 3'-UTR; NUFIP2 binds Roquin directly with high affinity, stabilizing NUFIP2, and acts as a cofactor for cooperative mRNA target recognition. RNAi screen (~1500 genes), co-immunoprecipitation, RNA-binding assays, ICOS 3'-UTR stem-loop mutagenesis, NUFIP2-Roquin binding assays Nature communications High 29352114
2008 In the germinal centre reaction, ICOS signaling acts upstream of CD40 and lymphotoxin beta receptor (LTβR): ICOS activation on T cells induces LTαβ on B cells in vitro; GC B cells from ICOS-/- mice show reduced LTαβ expression; agonistic anti-CD40 restores GC networks and LTαβ on GC B cells in ICOS-/- mice in a LTβR-dependent manner. ICOS-/- mice, in vitro T-B co-stimulation, agonistic antibody treatment, flow cytometry Journal of immunology High 18250437
2021 ICOS engagement in tissues (via ICOSL expressed in tissue) promotes establishment but not maintenance of CD8+ tissue-resident memory (Trm) T cells; this function requires ICOS-mediated PI3K signaling (IcosYF/YF knock-in mice show defective Trm generation); ICOS ligation during priming does not determine Trm induction—local tissue ICOS signaling during effector phase is the critical step. ICOS-/- and IcosYF/YF knock-in mice, Icosl-/- host transfers, ICOS-L blockade, adoptive transfer experiments, flow cytometry Immunity High 34932944
2018 The ICOS intracellular domain (ICD) enhances in vivo persistence of CAR-expressing CD4+ T cells, and a CAR combining ICOS and 4-1BB ICDs shows superior antitumor effects; the membrane-proximal ICD exerts dominant signaling, and optimal function requires the ICOS ICD linked to the ICOS transmembrane domain. CAR T-cell mouse tumor models, in vivo persistence assays, domain-swap constructs JCI insight High 29321369
2018 ICOS signaling (via the Tyr181-based PI3K-binding SH2 motif) is required for induction of collagen-induced arthritis including antibody production and expansion of inflammatory T cells, and for maintenance of CIA in an antibody-independent manner; glycolysis inhibition (3-bromopyruvate) ameliorates established CIA, linking ICOS-PI3K signaling to glucose metabolism. ICOS KO and PI3K-binding motif knock-in mice, collagen-induced arthritis model, glycolysis inhibitor treatment Journal of immunology High 29581356
2000 AILIM (rat ICOS ortholog) functions as a lymphocyte adhesion molecule; AILIM-transfected cells aggregate in an AILIM-dependent manner and human thymoma cells bind purified AILIM, suggesting an adhesion function for ICOS beyond co-stimulation. Cell aggregation assays, AILIM gene transfection, binding assays with purified protein International immunology Medium 10607749
2004 ICOS/AILIM signaling induces transendothelial migration and morphological polarization of memory/effector CD4+ T cells (but not naïve or Th2 cells) via interaction with B7h on TNF-α-treated endothelial cells, and is involved in Th1 cell trafficking into peripheral tissues. Transwell migration assays, T-cell polarization imaging, anti-ICOS/AILIM stimulation, human endothelial cell co-culture International immunology Medium 15339883
2012 ICOS signaling is required for generation and suppressive function of CD4+CD25+Foxp3+ regulatory T cells that convey respiratory tolerance; ICOS-/- Tregs produce significantly less IL-10 and fail to suppress airway inflammation when transferred to asthmatic recipients. ICOS-/- mice, anti-ICOSL blocking antibody, adoptive Treg transfer experiments, cytokine assays Journal of immunology High 22815292
2013 ICOS controls Foxp3+ Treg expansion and maintenance during helminth infection; ICOS deficiency increases Treg apoptosis, impairs Treg-specific IL-10 production, and prevents adaptive (Helios-) Treg responses in the intestinal lamina propria, with tissue-specific consequences on type 2 immunity. ICOS-/- mice infected with H. polygyrus or S. mansoni, flow cytometry, apoptosis assays, IL-10 intracellular staining European journal of immunology High 23319295
2005 ICOS co-stimulates invariant NKT (iNKT) cell activation; iNKT cells constitutively express ICOS and upregulate it after α-GalCer treatment; blockade of ICOS-ICOSL or ICOS gene knockout substantially inhibits α-GalCer-induced IFN-γ, IL-4 production, cytotoxic activity, and anti-metastatic effects; CD28 and ICOS act independently. ICOS-/- mice, anti-B7RP-1 mAb blockade, α-GalCer challenge, cytokine assays, cytotoxicity assays Biochemical and biophysical research communications High 15629449
2008 ICOS/ICOSL interaction is required for CD4+ iNKT cell function and homeostatic survival; ICOS-/- and ICOSL-/- mice have significantly fewer CD4+ iNKT cells; ICOS-/- iNKT cells fail to produce IL-4 and IL-13 upon activation and cannot reconstitute airway hyperreactivity; ICOSL-/- environment induces apoptosis of transferred WT iNKT cells. ICOS-/- and ICOSL-/- mice, adoptive transfer, α-GalCer challenge, apoptosis assays, cytokine assays Journal of immunology High 18390727
2011 ICOS-ICOSL signaling promotes skin wound healing by sustaining inflammatory cell infiltration and cytokine production (especially Th2 cytokines IL-4, IL-6, IL-10) at the wound site; ICOS-/-, ICOSL-/-, and double-KO mice each show equivalent delays in wound healing with suppressed keratinocyte migration, angiogenesis, and granulation tissue; IL-6 (but not IL-4) application restores early healing in KO mice. ICOS-/-, ICOSL-/-, and double-KO mice, excisional wound model, T-cell transfer/depletion, cytokine rescue experiments American journal of pathology High 21925472
2015 ICOS promotes activation of ILC2s in lungs: B7RP-1 co-culture increases ILC2 cytokine production; blocking ICOS/B7RP-1 interaction abrogates ILC2 expansion and eosinophil influx induced by papain; lung DCs express B7RP-1 and may serve as the ICOSL-expressing partner for ILC2s. ILC2 purification, B7RP-1-transfected cell co-culture, blocking mAb, papain-challenge mouse model, flow cytometry Biochemical and biophysical research communications Medium 26049110
2009 ICOS controls effector function (cytokine production and local proliferation) but not trafficking receptor expression (CXCR3, P-selectin ligand) of kidney-infiltrating CD4+ T cells in murine lupus; ICOS-/- MRL(lpr) effector cells migrate normally to CXCL9 but fail to produce inflammatory cytokines and show impaired in-situ proliferation. Genetic ablation (ICOS-/- MRL/lpr mice), chemokine/receptor flow cytometry, migration assays, cytokine assays Journal of immunology High 19299705
2021 ICOS signaling limits VAT-Treg accumulation and function in visceral adipose tissue via cell-intrinsic PI3K signaling; ICOS-/- mice and PI3K-binding knock-in mice show increased VAT-Treg abundance with elevated VAT-Treg markers, enhanced CCR3-dependent accumulation, reduced adipose inflammation, and improved insulin sensitivity on high-fat diet. ICOS-/- and IcosYF/YF knock-in mice, high-fat diet model, flow cytometry, CCR3 expression analysis Journal of experimental medicine High 33881452
2019 ICOSL (ICOS ligand) on non-immune podocytes contains an RGD motif that allows high-affinity, selective binding to αvβ3 integrin, limiting its activation; ICOSL deficiency in mice increases susceptibility to proteinuria rescued by recombinant ICOSL, revealing a renoprotective, immune-independent function of ICOSL as an endogenous αvβ3-selective antagonist. RGD motif mutagenesis, integrin binding assays, Icosl-/- mice, proteinuria models, recombinant ICOSL rescue Journal of clinical investigation High 30747722
2023 Intrathecal administration of an ICOS agonist antibody alleviates paclitaxel-induced neuropathic mechanical hypersensitivity in female mice via an IL-10-mediated mechanism in the dorsal root ganglion; blocking IL-10 receptor occludes the analgesic effect; ICOS agonism also reduces astrogliosis and satellite cell gliosis. Intrathecal ICOS agonist injection, IL-10R blocking antibody, spared nerve injury model, DRG IL-10 quantification, gliosis assessment Journal of neuroinflammation Medium 36774519
2019 Adipocyte-derived exosomal miR-27a-3p targets the ICOS 3'-UTR to suppress ICOS expression on T cells (confirmed by dual-luciferase reporter assay), reducing ICOS+ T-cell proliferation and IFN-γ secretion, providing a mechanism for obesity-associated enhancement of antitumor immunity. Dual-luciferase reporter assay (miR-27a-3p vs. ICOS 3'-UTR), exosome isolation, flow cytometry, IFN-γ ELISA Thoracic cancer Medium 32212417
2022 During inflammation, ICOSL upregulation on immunofibroblasts (and DCs) enables ICOS+ T-cell binding to induce LTα3 production, which drives chemokine production required for tertiary lymphoid structure (TLS) assembly via TNFRI/II engagement; pharmacological or genetic ICOS/ICOS-L blockade results in defective LTα expression and abrogates TLS formation. Genetic and pharmacological ICOS/ICOSL blockade, mouse and human tissue analysis, immunofibroblast-T cell co-culture Communications biology Medium 35508704
2016 ICOS triggering of osteoclast-expressed ICOSL (B7h) by recombinant ICOS-Fc inhibits RANKL-mediated osteoclast differentiation (suppressing NFATc1, DC-STAMP, OSCAR, TRAP, cathepsin K) and reduces bone loss in ovariectomized mice in vivo. ICOS-Fc treatment of human monocyte-derived osteoclast-like cells, osteolytic activity assays, ovariectomy mouse model Journal of immunology Medium 27798154

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 1156 9930702
1999 T-cell co-stimulation through B7RP-1 and ICOS. Nature 614 10617205
2003 Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nature immunology 541 12577056
2001 ICOS is essential for effective T-helper-cell responses. Nature 514 11343123
2018 Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI insight 462 29321369
2013 Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility. Nature 325 23619696
2000 Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. Journal of immunology (Baltimore, Md. : 1950) 323 11046032
2003 Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nature reviews. Immunology 285 12876557
2015 ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2. The Journal of experimental medicine 246 25646266
2014 Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. The Journal of experimental medicine 240 24687957
2016 ICOS Co-Stimulation: Friend or Foe? Frontiers in immunology 234 27559335
2015 ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 202 25692700
2014 IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. The Journal of clinical investigation 201 24292706
2003 Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. The Journal of experimental medicine 195 12538658
2010 Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS). Current opinion in immunology 175 20116985
2015 Agonists of Co-stimulation in Cancer Immunotherapy Directed Against CD137, OX40, GITR, CD27, CD28, and ICOS. Seminars in oncology 168 26320067
2010 Inducible costimulator (ICOS) is a marker for highly suppressive antigen-specific T cells sharing features of TH17/TH1 and regulatory T cells. The Journal of allergy and clinical immunology 143 20624644
2000 Induction, binding specificity and function of human ICOS. European journal of immunology 138 11169414
2020 Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren's syndrome with ectopic germinal centres and MALT lymphoma. Annals of the rheumatic diseases 134 32963045
2020 The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy. ESMO open 130 32516116
2003 The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity. The Journal of clinical investigation 116 12865411
2015 ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis. The Journal of experimental medicine 103 25918344
2013 ICOS controls Foxp3(+) regulatory T-cell expansion, maintenance and IL-10 production during helminth infection. European journal of immunology 96 23319295
2020 ICOS Is an Indicator of T-cell-Mediated Response to Cancer Immunotherapy. Cancer research 95 32156777
2019 Role of Inducible Co-Stimulator (ICOS) in cancer immunotherapy. Expert opinion on biological therapy 94 31738626
2001 ICOS costimulation requires IL-2 and can be prevented by CTLA-4 engagement. Journal of immunology (Baltimore, Md. : 1950) 87 11290772
2021 Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8+ tissue-resident memory T cells. Immunity 85 34932944
2016 OX40 Cooperates with ICOS To Amplify Follicular Th Cell Development and Germinal Center Reactions during Infection. Journal of immunology (Baltimore, Md. : 1950) 84 27895177
2012 ICOS mediates the generation and function of CD4+CD25+Foxp3+ regulatory T cells conveying respiratory tolerance. Journal of immunology (Baltimore, Md. : 1950) 82 22815292
2003 Regulation of immune and autoimmune responses by ICOS. Journal of autoimmunity 75 14599850
2016 The clinical impact of ICOS signal in colorectal cancer patients. Oncoimmunology 74 27467961
2008 ICOS/ICOSL interaction is required for CD4+ invariant NKT cell function and homeostatic survival. Journal of immunology (Baltimore, Md. : 1950) 72 18390727
2018 Inducible Co-Stimulator (ICOS) as a potential therapeutic target for anti-cancer therapy. Expert opinion on therapeutic targets 68 29468927
2009 The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency. Immunological reviews 68 19426217
2022 PD-1 and ICOS coexpression identifies tumor-reactive CD4+ T cells in human solid tumors. The Journal of clinical investigation 67 35439168
2020 Molecular Imaging of Chimeric Antigen Receptor T Cells by ICOS-ImmunoPET. Clinical cancer research : an official journal of the American Association for Cancer Research 67 33087332
2001 ICOS ligand costimulation is required for T-cell encephalitogenicity. Clinical immunology (Orlando, Fla.) 58 11513541
2006 CD28 and ICOS: similar or separate costimulators of T cells? Immunology letters 57 16580736
2016 IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection. PLoS pathogens 53 27812214
2015 The Costimulatory Molecule ICOS Regulates Host Th1 and Follicular Th Cell Differentiation in Response to Plasmodium chabaudi chabaudi AS Infection. Journal of immunology (Baltimore, Md. : 1950) 50 26667167
2007 Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice. Clinical immunology (Orlando, Fla.) 47 17889619
2005 Renal tubular epithelial cells modulate T-cell responses via ICOS-L and B7-H1. Kidney international 46 16221208
2023 Tumor-infiltrating mast cells stimulate ICOS+ regulatory T cells through an IL-33 and IL-2 axis to promote gastric cancer progression. Journal of advanced research 45 37086778
2021 Vaccine-induced ICOS+CD38+ circulating Tfh are sensitive biosensors of age-related changes in inflammatory pathways. Cell reports. Medicine 45 34095875
2004 The role of ICOS and other costimulatory molecules in allergy and asthma. Springer seminars in immunopathology 44 14999428
2003 Expression and function of the co-stimulator H4/ICOS on activated T cells of patients with rheumatoid arthritis. The Journal of rheumatology 44 12784384
2021 Microwave ablation induces Th1-type immune response with activation of ICOS pathway in early-stage breast cancer. Journal for immunotherapy of cancer 42 33795388
2020 Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies. Nature communications 41 33033255
2006 Regulation of mouse inducible costimulator (ICOS) expression by Fyn-NFATc2 and ERK signaling in T cells. The Journal of biological chemistry 41 16880206
2006 ICOS cooperates with CD28, IL-2, and IFN-gamma and modulates activation of human naïve CD4+ T cells. European journal of immunology 38 17013990
2000 AILIM/ICOS: a novel lymphocyte adhesion molecule. International immunology 38 10607749
2016 ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Vivo. Journal of immunology (Baltimore, Md. : 1950) 37 27798154
2000 The T cell activation molecule H4 and the CD28-like molecule ICOS are identical. European journal of immunology 37 11093165
2015 ICOS promotes group 2 innate lymphoid cell activation in lungs. Biochemical and biophysical research communications 36 26049110
2009 ICOS controls effector function but not trafficking receptor expression of kidney-infiltrating effector T cells in murine lupus. Journal of immunology (Baltimore, Md. : 1950) 36 19299705
2006 CD28/CTLA-4--CD80/CD86 and ICOS--B7RP-1 costimulatory pathway in bronchial asthma. Allergy 36 16364152
2020 An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression. Cancer immunology research 35 32999002
2019 Blockade of CTLA-4 and PD-1 Enhances Adoptive T-cell Therapy Efficacy in an ICOS-Mediated Manner. Cancer immunology research 35 31466995
2011 Inducible costimulator (ICOS) and ICOS ligand signaling has pivotal roles in skin wound healing via cytokine production. The American journal of pathology 35 21925472
2005 ICOS costimulates invariant NKT cell activation. Biochemical and biophysical research communications 35 15629449
2015 A pilot trial targeting the ICOS-ICOS-L pathway in nonhuman primate kidney transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 34 25703015
2005 Regulation of immune and autoimmune responses by ICOS-B7h interaction. Clinical immunology (Orlando, Fla.) 34 15870016
2018 Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA. Nature communications 33 29352114
2003 The immunological synapse for B-cell memory: the role of the ICOS and its ligand for the longevity of humoral immunity. Current opinion in allergy and clinical immunology 32 14612664
2018 Transmembrane domain-mediated Lck association underlies bystander and costimulatory ICOS signaling. Cellular & molecular immunology 31 30523347
2003 Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways. European journal of immunology 31 12594849
2024 ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype. The Journal of experimental medicine 30 38517331
2020 Immunotherapy of experimental melanoma with ICOS-Fc loaded in biocompatible and biodegradable nanoparticles. Journal of controlled release : official journal of the Controlled Release Society 29 31962094
2022 Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction. Communications biology 28 35508704
2021 The ubiquitin ligase Peli1 inhibits ICOS and thereby Tfh-mediated immunity. Cellular & molecular immunology 28 33707688
2021 Bacteroides thetaiotaomicron Ameliorates Experimental Allergic Airway Inflammation via Activation of ICOS+Tregs and Inhibition of Th2 Response. Frontiers in immunology 28 33815374
2020 Exosome miR-27a-3p secreted from adipocytes targets ICOS to promote antitumor immunity in lung adenocarcinoma. Thoracic cancer 28 32212417
2019 CXCR5+PD1+ICOS+ Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation. Frontiers in immunology 28 31552030
2023 Inducible co-stimulatory molecule (ICOS) alleviates paclitaxel-induced neuropathic pain via an IL-10-mediated mechanism in female mice. Journal of neuroinflammation 27 36774519
2020 ICOS is widely expressed in cutaneous T-cell lymphoma, and its targeting promotes potent killing of malignant cells. Blood advances 27 33095875
2020 Transcriptome Sequencing Reveals Potential Roles of ICOS in Primary Sjögren's Syndrome. Frontiers in cell and developmental biology 26 33344450
2018 ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis. Journal of immunology (Baltimore, Md. : 1950) 26 29581356
2008 ICOS, CD40, and lymphotoxin beta receptors signal sequentially and interdependently to initiate a germinal center reaction. Journal of immunology (Baltimore, Md. : 1950) 26 18250437
2001 AILIM/ICOS: its expression and functional analysis with monoclonal antibodies. Hybridoma and hybridomics 26 11839247
2021 ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue. The Journal of experimental medicine 25 33881452
2019 Nonimmune cell-derived ICOS ligand functions as a renoprotective αvβ3 integrin-selective antagonist. The Journal of clinical investigation 25 30747722
2006 Regulation of T:B cell interactions by the inducible costimulator molecule: does ICOS "induce" disease? Clinical immunology (Orlando, Fla.) 25 16790364
2004 AILIM/ICOS signaling induces T-cell migration/polarization of memory/effector T-cells. International immunology 25 15339883
2016 Loss of Immune Tolerance Is Controlled by ICOS in Sle1 Mice. Journal of immunology (Baltimore, Md. : 1950) 24 27296665
2019 Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency. Journal of clinical immunology 23 31858365
2006 A critical role for ICOS co-stimulation in immune containment of pulmonary influenza virus infection. European journal of immunology 22 17039567
2022 Acazicolcept (ALPN-101), a dual ICOS/CD28 antagonist, demonstrates efficacy in systemic sclerosis preclinical mouse models. Arthritis research & therapy 21 34986869
2016 Inducible costimulator (ICOS) potentiates TCR-induced calcium flux by augmenting PLCγ1 activation and actin remodeling. Molecular immunology 21 27693916
2006 The role of the ICOS/B7RP-1 T cell costimulatory pathway in murine experimental autoimmune uveoretinitis. European journal of immunology 21 17039566
2019 ICOS deficiency hampers the homeostasis, development and function of NK cells. PloS one 20 31283790
2018 Leptin Upregulates Peripheral CD4+CXCR5+ICOS+ T Cells via Increased IL-6 in Rheumatoid Arthritis Patients. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20 29377743
2012 CD4⁺Foxp3⁺ Treg and its ICOS⁺ subsets in patients with myocardial infarction. Iranian journal of immunology : IJI 20 22426168
2007 ICOS and B7 costimulatory molecule expression identifies activated cellular subsets in rheumatoid arthritis. Cytometry. Part A : the journal of the International Society for Analytical Cytology 20 17323353
2012 Augmented ICOS expression in patients with early diffuse cutaneous systemic sclerosis. Rheumatology (Oxford, England) 19 23024058
2024 Discovery of ICOS-Targeted Small Molecules Using Affinity Selection Mass Spectrometry Screening. ChemMedChem 18 39269728
2018 PD-1 blockade augments humoral immunity through ICOS-mediated CD4+ T cell instruction. International immunopharmacology 18 30448635
2015 ICOS is required for the generation of both central and effector CD4(+) memory T-cell populations following acute bacterial infection. European journal of immunology 18 25754933
2012 ICOS-LICOS interaction is critically involved in TGN1412-mediated T-cell activation. Blood 18 22577174
2007 ICOS gene haplotypes correlate with IL10 secretion and multiple sclerosis evolution. Journal of neuroimmunology 18 17481737
2006 Genetic variation in ICOS regulates mRNA levels of ICOS and splicing isoforms of CTLA4. Molecular immunology 18 16996590