Affinage

ICOS

Inducible T-cell costimulator · UniProt Q9Y6W8

Length
199 aa
Mass
22.6 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ICOS (CD278) is an inducibly expressed, disulfide-linked homodimeric T-cell co-stimulatory receptor that shapes T-dependent humoral immunity, helper and regulatory T-cell differentiation, and effector/memory CD8 programs (PMID:9930702, PMID:11343121). Unlike the constitutively expressed CD28, ICOS is induced upon T-cell activation and binds a distinct B7-family ligand, ICOSL (B7RP-1/B7h), rather than B7-1/B7-2 (PMID:9930702, PMID:10617205, PMID:11343123); a 3.3 Å crystal structure defines this specificity through a central FDPPPF motif, CC' loop residues, and the N110 glycan at the ICOS:ICOSL interface (PMID:33033255). Ligation triggers signaling through two coupled modules: the transmembrane domain recruits Lck, which is required for PI3K activation and calcium mobilization, while the phosphorylated cytoplasmic YMFM/Tyr motif selectively recruits class IA PI3K with preferential engagement of p110α, driving PI3K/Akt and MAP kinase (ERK, JNK, p38) cascades that super-induce IL-10 and IL-4 but not IL-2 (PMID:30523347, PMID:21188463, PMID:14550257, PMID:9930702). These signals also reorganize the actin cytoskeleton via Rho/ROCK/PAK to drive T-cell elongation and migration, and direct intra-organ positioning by promoting follicular recruitment of helper T cells independently of co-stimulation (PMID:17077177, PMID:23619696). ICOS sits atop a transcriptional program for follicular helper T (Tfh) cell fate: it induces Bcl6 to commit cells to the Tfh lineage (PMID:21636296) and maintains the Tfh homing phenotype through a Foxo1-dependent suppression of Klf2 that sustains CXCR5 and other homing receptors (PMID:25646266). Beyond Tfh, ICOS supports germinal center formation and immunoglobulin class switching (PMID:11343123), T follicular regulatory cell differentiation (PMID:36754569), ILC2 survival and type-2 cytokine output via STAT5 (PMID:25769613), iNKT homeostasis (PMID:18390727), and CD8+ tissue-resident memory establishment via PI3K signaling (PMID:34932944), while restraining regulatory T cells in adipose tissue and limiting CD8+ T-cell quality during chronic antigen exposure through FoxO1 (PMID:33881452, PMID:40628269). ICOS abundance is tightly controlled post-transcriptionally by Roquin and its cofactor NUFIP2, which cooperatively bind 3'-UTR stem-loops to promote mRNA decay (PMID:29352114, PMID:19217324), and transcriptionally by NFAT, c-Rel (limited by the Peli1 ubiquitin ligase), STAT3, and intronic CpG methylation (PMID:18988696, PMID:33707688, PMID:21765024). Its signaling has been harnessed therapeutically as a CAR intracellular domain that enhances T-cell persistence and TH17/TH1 polarization (PMID:24986688, PMID:29321369).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Established ICOS as a distinct, inducible T-cell co-stimulatory receptor separate from the CD28 pathway, defining the existence of a new co-stimulation axis with a unique cytokine signature.

    Evidence Molecular cloning, cell-surface expression, T-cell co-stimulation and cytokine assays; receptor-ligand binding to B7RP-1 in mouse

    PMID:10617205 PMID:9930702

    Open questions at the time
    • Ligand identity initially defined functionally before structural interface was known
    • Signaling mechanism downstream of receptor not yet defined
  2. 2000 Medium

    Confirmed ICOS as a glycosylated disulfide-linked homodimer and identified B7h/B7RP-1 as its ligand, and showed the receptor can mediate homotypic cell adhesion.

    Evidence Immunoprecipitation, chromosomal mapping, ICOS-Ig fusion binding; transfection-based cell aggregation in rat ortholog (AILIM)

    PMID:10607749 PMID:10760791

    Open questions at the time
    • Adhesion function shown in single lab with rat ortholog
    • Physiological relevance of adhesion vs co-stimulation unresolved
  3. 2001 High

    Genetic loss-of-function defined ICOS as essential for T-dependent humoral immunity, establishing its role in germinal center formation, class switching, and Th2 cytokine production.

    Evidence Two independent ICOS knockout mouse lines; immunization, germinal center histology, isotype and cytokine measurements; antibody-based dissection of CTLA-4 cross-regulation

    PMID:11290772 PMID:11343121 PMID:11343123

    Open questions at the time
    • Molecular signaling explaining the cytokine bias not yet established
    • Cell-intrinsic vs help-dependent contributions not separated
  4. 2003 Medium

    Mapped ICOS to PI3K/Akt and MAP kinase signaling, showing distinct branches govern proliferation versus IL-10 production and differentiating ICOS from CD28 signaling.

    Evidence Pharmacological kinase inhibitors, co-IP of PI3K with ICOS, cytochalasin D actin disruption in T/Th2 cells

    PMID:12594849 PMID:14550257

    Open questions at the time
    • Inhibitor-based, single-lab dissection
    • Direct PI3K recruitment motif not yet mapped at residue level
  5. 2006 Medium

    Linked ICOS signaling to actin-based T-cell motility, showing PI3K/Akt-dependent cytoskeletal reorganization through Rho/ROCK/PAK drives elongation and transendothelial migration.

    Evidence ICOS stimulation of activated T cells with PI3K inhibitors, PIP3 imaging, dominant-negative Rho constructs, migration assays

    PMID:17077177

    Open questions at the time
    • Single-lab pathway dissection
    • In vivo migratory relevance not yet tested at this stage
  6. 2009 High

    Placed ICOS within a regulatory circuit, showing Roquin constrains ICOS signaling and that dysregulated ICOS drives CD28-independent Tfh and germinal center responses.

    Evidence Roquin mutant mouse with ICOS-/- genetic epistasis; T-cell subset and germinal center analysis

    PMID:19217324

    Open questions at the time
    • Molecular basis of Roquin-mediated ICOS repression not yet defined
    • Direct vs indirect control unresolved at this stage
  7. 2010 High

    Resolved the biochemical basis of ICOS-PI3K coupling, showing the phosphorylated YMFM motif preferentially recruits p110α with distinct functional roles for PI3K catalytic isoforms.

    Evidence Phosphopeptide pulldowns, co-IP, isoform-selective siRNA and inhibitors, ERK/Akt and cell elongation readouts

    PMID:21188463

    Open questions at the time
    • Mechanism dissected in cell lines/primary T cells, not structural
    • In vivo isoform selectivity not established here
  8. 2011 High

    Defined ICOS as the early signal initiating the Tfh transcriptional program through Bcl6 induction, and identified STAT3/methylation control of ICOS transcription in lymphoma.

    Evidence In vivo viral infection with flow cytometry for Bcl6/CXCR5/Blimp1; NPM-ALK/STAT3 reporter and methylation assays

    PMID:21636296 PMID:21765024

    Open questions at the time
    • How ICOS signaling mechanistically induces Bcl6 not fully traced
    • Lymphoma transcriptional findings are single-lab reporter-based
  9. 2013 High

    Established a co-stimulation-independent function for ICOS, showing it directly drives follicular recruitment and persistent motility of helper T cells via bystander ICOSL engagement.

    Evidence Intravital two-photon imaging with ICOSL-deficient bystander B cells and Bcl6-independent genetic dissection

    PMID:23619696

    Open questions at the time
    • Signaling module enabling bystander motility not yet defined at this stage
  10. 2015 High

    Defined the mechanism by which ICOS maintains the Tfh phenotype (Foxo1-mediated Klf2 suppression controlling homing receptors) and extended ICOS function to ILC2 survival via STAT5.

    Evidence ICOS blockade in vivo, Klf2 ChIP at homing-receptor loci; ICOS/ICOSL knockouts and human blockade with STAT5 phosphorylation readouts

    PMID:25646266 PMID:25769613

    Open questions at the time
    • Connection between proximal PI3K signaling and Foxo1 regulation not fully linear
    • STAT5 activation mechanism downstream of ICOS in ILC2 not detailed
  11. 2018 High

    Assigned the proximal signaling architecture, showing the ICOS transmembrane domain recruits Lck to enable PI3K activation, and defined Roquin/NUFIP2 cooperative 3'-UTR repression of ICOS mRNA.

    Evidence TMD replacement/knockin mutagenesis with Lck co-IP and calcium/PI3K and in vivo Tfh readouts; RNAi screen, NUFIP2-Roquin co-IP, 3'-UTR stem-loop reporter mutagenesis

    PMID:29352114 PMID:30523347

    Open questions at the time
    • Stoichiometry of TMD-Lck-PI3K assembly not structurally resolved
    • How Roquin/NUFIP2 selects ICOS among targets not fully defined
  12. 2018 High

    Demonstrated that ICOS PI3K-coupled signaling is required for both induction and antibody-independent maintenance of autoimmune arthritis and intersects with glycolytic metabolism.

    Evidence ICOS knockout and Tyr181 PI3K-signaling knockin mice in collagen-induced arthritis; glycolysis inhibitor treatment

    PMID:29581356

    Open questions at the time
    • Mechanism connecting ICOS-PI3K to glycolysis not directly defined
    • Disease-specific cell types responsible not fully resolved
  13. 2019 Medium

    Showed ICOS co-stimulation is required for efficacy of combined checkpoint blockade and for CD8+ effector molecule programming.

    Evidence ICOS-/- PMEL-1 CD8+ adoptive transfer with dual CTLA-4/PD-1 blockade; tumor growth and Eomes/IFN-γ/perforin analysis

    PMID:31466995

    Open questions at the time
    • Single-lab loss-of-function
    • Direct vs indirect effect on Eomes not separated
  14. 2021 High

    Defined context-dependent ICOS functions across CD8+ tissue-resident memory establishment, T follicular regulatory differentiation, and restraint of adipose Treg through cell-intrinsic PI3K signaling.

    Evidence IcosYF/YF PI3K-signaling knockin and conditional knockouts; adoptive transfer, single-cell transcriptomics, NFAT2 localization, metabolic readouts

    PMID:33707688 PMID:33881452 PMID:34932944 PMID:36754569

    Open questions at the time
    • Why ICOS-PI3K promotes some lineages while restraining others not mechanistically unified
    • Tissue-specific ICOSL source contributions still being mapped
  15. 2025 High

    Revealed a restraining role for sustained ICOS signaling during chronic antigen exposure, where ICOS deficiency potentiates FoxO1 and improves CD8+ T-cell quality and PD-1 blockade response.

    Evidence ICOS-/- chronic LCMV and tumor models; FoxO1 activity and single-cell analysis; ICOSL blockade with PD-1 combination

    PMID:40628269

    Open questions at the time
    • Threshold/duration distinguishing beneficial from limiting ICOS signaling unclear
    • Mechanistic link between ICOS PI3K and FoxO1 suppression in exhaustion not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single ICOS-PI3K/Lck signaling module is differentially decoded to produce opposing outcomes (promoting Tfh/Trm yet restraining adipose Treg and chronic CD8 responses) across cell types and contexts remains unresolved.
  • No unifying model linking signal strength/duration to divergent transcriptional outputs
  • Structural basis of TMD-Lck-PI3K assembly undefined
  • Context-dependent ICOSL source and timing requirements incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0048018 receptor ligand activity 2 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
ICOSLLCKNUFIP2PIK3CAPIK3R1ROQUIN

Evidence

Reading pass · 32 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 (55-60 kDa) that is inducibly expressed on T cells (unlike constitutively expressed CD28), binds a distinct ligand (not B7-1/B7-2), enhances T-cell proliferation, lymphokine secretion, and B-cell help, super-induces IL-10 but does not upregulate IL-2 production. Molecular cloning, cell surface expression studies, T-cell co-stimulation assays, cytokine production assays, immunohistochemistry of tonsil Nature High 9930702
1999 ICOS (murine homolog) binds specifically to B7RP-1 (B7-related protein-1), a B7-family ligand expressed on B cells and macrophages; ICOS and B7RP-1 do not interact with proteins in the CD28-B7 pathway, and B7RP-1 co-stimulates T cells independently of CD28. Receptor-ligand binding assays, T-cell co-stimulation in vitro, transgenic mouse overexpression of B7RP-1-Fc Nature High 10617205
2000 Murine ICOS is expressed as a disulfide-linked, glycosylated homodimer of 47-57 kDa on the T-cell surface; its gene maps to mouse chromosome 1 in the same region as CD28 and CTLA-4; B7h is identified as a ligand for muICOS using recombinant chimeric muICOS-Ig. Molecular cloning, immunoprecipitation, flow cytometry with monoclonal antibodies, chromosomal mapping, muICOS-Ig binding assay European journal of immunology High 10760791
2000 AILIM (rat ICOS homolog) functions as a lymphocyte adhesion molecule; cells transfected with the AILIM gene aggregate in an AILIM-dependent manner, indicating ICOS/AILIM can mediate cell-cell adhesion. Transfection-based cell aggregation assay, cell binding assay International immunology Medium 10607749
2001 ICOS deficiency in mice results in defective T-cell activation and proliferation, failure of ICOS-/- T cells to produce IL-4 in vitro and in vivo, severely impaired humoral immune responses, and enhanced susceptibility to experimental autoimmune encephalomyelitis. ICOS knockout mouse generation; in vitro T-cell activation/proliferation assays; in vivo immunization; cytokine production assays Nature High 11343121
2001 ICOS-deficient mice show severely deficient T-cell-dependent B-cell responses in vivo: germinal center formation is impaired, immunoglobulin class switching (including IgE) is defective, and ICOS-/- T cells produce only low levels of IL-4 but remain competent to produce IFN-γ. ICOS binds specifically to B7RP-1 but not B7-1 or B7-2. ICOS gene-targeted knockout mice; in vivo immunization; germinal center histology; immunoglobulin isotype measurement; cytokine assays; B7 ligand binding specificity assay Nature High 11343123
2001 CTLA-4 ligation blocks ICOS costimulation by two mechanisms: (1) indirectly preventing induction of ICOS cell surface expression on resting cells, and (2) directly blocking ICOS-mediated cytokine induction (IL-4, IL-10, IL-13) on preactivated cells with high ICOS expression. IL-2 overcomes both mechanisms and is required for sustained ICOS-costimulated T-cell proliferation. Anti-CD3/anti-ICOS/anti-CTLA-4 magnetic bead stimulation assays; cytokine measurement; IL-2 supplementation/blocking experiments Journal of immunology Medium 11290772
2003 ICOS cytoplasmic tail engages PI3-kinase via its YMFM motif; ICOS costimulation activates PI3-kinase/Akt and MAP kinase (ERK1/2, JNK, p38) pathways. PI3-kinase and ERK1/2 regulate T-cell proliferation through both ICOS and CD28; Akt and p38 regulate IL-10 production but not proliferation, distinguishing ICOS signaling from CD28 for cytokine production. Pharmacological inhibitors of PI3K, Akt, ERK, JNK, p38, JAK; T-cell proliferation and cytokine assays Biochemical and biophysical research communications Medium 14550257
2003 H4/ICOS costimulation enhances CD3-mediated tyrosine phosphorylation of ZAP-70, ζ chain, and Vav, activates ERK, JNK, and p38 MAP kinases. PI3-K association with H4/ICOS is enhanced upon cross-linking; PI3-K inhibitors block ERK and JNK activation and IL-4/IL-10 secretion. Actin polymerization is required for ZAP-70 and MAP kinase activation downstream of ICOS. Immunoprecipitation of H4/ICOS with PI3-K; western blot for kinase phosphorylation; pharmacological inhibitors; cytochalasin D treatment; cytokine assays in mouse CD4+ Th2 cells European journal of immunology Medium 12594849
2009 Roquin (E3 ubiquitin ligase) normally constrains ICOS signaling; Roquin mutation causes CD28-independent, ICOS-dependent generation of follicular helper T cells, germinal center formation, and regulatory T cell homeostasis, demonstrating that Roquin functionally compartmentalizes ICOS and CD28 signals. Roquin mutant mouse model; genetic epistasis (ICOS-/- × Roquin mutant); T-cell subset analysis; germinal center assays Immunity High 19217324
2011 ICOS provides a critical early signal to induce the transcription factor Bcl6 during DC priming; Bcl6 then induces CXCR5, driving follicular helper T (Tfh) cell differentiation. Tfh vs. effector Th bifurcation is measurable by day 2 after infection, defined by IL-2Rα levels and differential Bcl6/Blimp1 expression. B cells are required for maintenance of Bcl6 and Tfh commitment via sequential ICOS signals. In vivo acute viral infection model; flow cytometry for Bcl6, CXCR5, Blimp1 expression; ICOS receptor signaling manipulation; B cell-deficient mouse analysis Immunity High 21636296
2011 NPM-ALK oncogenic kinase induces ICOS expression in T-cell lymphoma via STAT3, which transcriptionally activates the ICOS gene promoter and suppresses miR-219 (which otherwise inhibits ICOS expression). DNA methylation of a CpG island in ICOS intron 1 modulates ICOS transcriptional activity. NPM-ALK inhibition/expression; STAT3 reporter assays; miR-219 functional assays; DNA methyltransferase inhibitor treatment; ICOS promoter luciferase assay Blood Medium 21765024
2013 ICOS directly controls follicular recruitment of activated T-helper cells independently of ICOSL-mediated co-stimulation by DCs or cognate B cells, and independently of Bcl6-mediated programming. ICOS engagement by ICOSL on follicular bystander B cells drives coordinated pseudopod formation and promotes persistent T-cell migration at the T-cell zone/B-cell follicle border. In vivo mouse models with ICOSL-deficient bystander B cells; intravital two-photon dynamic imaging; Bcl6-independent genetic dissection Nature High 23619696
2015 ICOS co-stimulation maintains Tfh cell phenotype by suppressing Klf2 via Foxo1 signaling. Klf2 directly binds to Cxcr5, Ccr7, Psgl-1, and S1pr1 gene loci; low Klf2 is essential to maintain the Tfh homing receptor pattern. ICOS blockade causes relocation of Tfh cells to the T-cell zone and phenotypic reversion. ICOS blockade in vivo; Klf2 ChIP binding to target gene loci; Foxo1 signaling analysis; flow cytometry for homing receptors and Tfh markers The Journal of experimental medicine High 25646266
2015 ICOS:ICOS-ligand interaction in ILC2s promotes cytokine production (IL-5, IL-13) and survival through STAT5 signaling. ILC2s express both ICOS and ICOS-ligand, enabling autocrine/homotypic signaling. ICOS-/- and ICOSL-/- mouse models; human ILC2 ICOS blockade; STAT5 phosphorylation assays; airway hyperreactivity readout Immunity High 25769613
2018 The transmembrane domain (TMD) of ICOS, not its cytoplasmic domain, mediates association with the tyrosine kinase Lck, which is required for PI3K activation (p85 recruitment) and augmentation of calcium mobilization. TMD-enabled Lck association is required for both bystander and costimulatory ICOS signaling, and for TFH development and GC formation in vivo. TMD replacement/mutation constructs; co-immunoprecipitation of Lck with ICOS TMD; calcium flux assays; PI3K activation assays; in vivo Tfh/GC analysis with TMD-mutant knockin mice Cellular & molecular immunology High 30523347
2018 Post-transcriptional repression of human ICOS mRNA by Roquin proteins requires two neighboring non-canonical stem-loops in the ICOS 3'-UTR. NUFIP2, identified as a Roquin cofactor, binds directly to Roquin with high affinity and cooperatively binds these ICOS 3'-UTR stem-loop structures with Roquin to promote mRNA decay. RNA interference screen (~1500 genes); NUFIP2-Roquin co-immunoprecipitation; RNA binding assays; ICOS 3'-UTR reporter assays; mutagenesis of stem-loops Nature communications High 29352114
2020 Crystal structure of the ICOS/ICOS-L immune complex at 3.3 Å resolution reveals that a central FDPPPF motif and CC' loop residues of ICOS are responsible for specificity of ICOS-L binding, with a distinct receptor binding orientation compared to other CD28 family members. The ICOS N110 N-linked glycan participates in ICOS-L binding. Therapeutic antibodies under clinical evaluation mimic receptor-ligand core binding interactions. X-ray crystallography of ICOS/ICOS-L complex and antibody-bound complexes; binding affinity measurements; mutagenesis Nature communications High 33033255
2010 Phosphorylated ICOS YMFM motif (Y191) selectively recruits class IA PI3K regulatory subunits (p85α, p50-55α, p85β) and catalytic subunits, with preferential co-precipitation of p110α over p110δ. Silencing p110α enhances ERK activation while silencing p110δ inhibits it; p110α-specific inhibitors block ICOS-induced cell elongation whereas p110δ inhibitors do not, showing distinct roles of PI3K catalytic subunits in ICOS signaling. Phosphopeptide pulldown assays; co-immunoprecipitation; siRNA silencing of p110α and p110δ; isoform-selective PI3K inhibitors; ERK/Akt activation assays; cell elongation assay Cellular and molecular life sciences High 21188463
2006 ICOS/AILIM signaling induces morphological polarization (elongation) and transendothelial migration of activated memory/effector CD4+ T cells (but not naive T cells) via PI3-kinase/Akt-dependent PIP3 localization to lamellipodia and actin cytoskeleton reorganization, requiring Rho family members, ROCK, and PAK1/PAK3 as downstream effectors. AILIM/ICOS stimulation of activated T cells; PI3K/Akt inhibitors; PIP3 localization imaging; dominant-negative Rho GTPase constructs; PAK1/PAK3 phosphorylation analysis; transendothelial migration assay International immunology Medium 17077177
2008 ICOS/ICOSL interaction is required for CD4+ invariant NKT cell function, homeostasis, and peripheral survival; ICOS-/- iNKT cells fail to produce IL-4 and IL-13 upon activation and cannot reconstitute airway hyperreactivity. ICOS-/- iNKT cells undergo increased apoptosis in ICOSL-/- recipients. ICOS-/- and ICOSL-/- mouse models; adoptive transfer into iNKT-deficient mice; cytokine assays; AHR readout; apoptosis assays Journal of immunology High 18390727
2014 CAR T cells with the ICOS intracellular domain (ICD) generate IL-17-producing TH17/TH1 bipolar effector cells with enhanced persistence. ICOS ICD increases expression of RORC, CD161, IL1R-1, NCS1 and also induces IFN-γ and T-bet, consistent with TH17/TH1 bipolarization; ICOS ICD outperforms CD28 and 4-1BB ICDs for TH17 cell persistence. CAR T-cell construction with ICOS ICD; cytokine profiling; transcriptional analysis; in vivo tumor model with adoptive T-cell transfer Blood Medium 24986688
2018 The ICOS ICD dramatically enhances in vivo persistence of CAR-expressing CD4+ T cells. In third-generation CARs, combining ICOS and 4-1BB ICDs shows superior antitumor effects; the membrane-proximal ICD exerts a dominant effect. The ICOS ICD must be positioned proximal to the cell membrane and linked to the ICOS transmembrane domain for optimal persistence and antitumor benefits. CAR T-cell construction with varied ICD combinations; in vivo solid tumor models; persistence tracking; domain position swapping experiments JCI insight Medium 29321369
2021 ICOS signaling promotes establishment (but not maintenance) of CD8+ tissue-resident memory (Trm) T cells via PI3K signaling (IcosYF/YF knockin mice are defective). ICOS ligation is required in peripheral tissues during the effector phase, not during priming; local ICOSL expression by non-hematopoietic cells in tissue drives Trm generation. ICOS-/- and IcosYF/YF (PI3K-signaling mutant) adoptive transfer; ICOSL blockade; Icosl-/- recipient mice; flow cytometry for Trm markers Immunity High 34932944
2021 ICOS signaling limits accumulation and function of regulatory T cells specifically in visceral adipose tissue (VAT) via cell-intrinsic PI3K signaling. ICOS-/- mice and IcosYF/YF knockin mice (PI3K signaling-deficient ICOS) have increased VAT-Treg abundance, elevated CCR3 expression, elevated VAT-Treg markers, reduced adipose inflammation, and heightened insulin sensitivity under high-fat diet. ICOS-/- and IcosYF/YF knockin mice on high-fat diet; VAT Treg flow cytometry; CCR3 expression analysis; insulin tolerance tests The Journal of experimental medicine High 33881452
2018 ICOS signaling via the Tyr181-based SH2-binding motif (activating PI3K) is critical for both induction and maintenance of collagen-induced arthritis (CIA): required for antibody production and inflammatory T-cell expansion during induction, and for Ab-independent maintenance. ICOS signaling overlaps with glycolytic pathways, as 3-bromopyruvate (glycolysis inhibitor) ameliorates established CIA. ICOS knockout and PI3K-signaling knockin (Tyr181 mutant) mouse models; CIA model; antibody titers; T-cell expansion assays; glycolysis inhibitor treatment Journal of immunology High 29581356
2008 Delta-9-tetrahydrocannabinol (THC) suppresses ICOS expression in activated T cells at the transcriptional level, at least in part by downregulating NFAT transcriptional activity, as shown by ICOS promoter luciferase reporter assays and NFAT reporter assays. ICOS mRNA quantification; ICOS promoter-luciferase reporter assay; NFAT reporter assay; anti-CD3/CD28 stimulation of primary T cells Journal of leukocyte biology Medium 18988696
2021 ICOS costimulation is indispensable for T follicular regulatory (Tfr) cell differentiation: Foxp3-Cre-mediated ICOS knockout drastically reduces Tfr cells during GC reactions. Mechanistically, ICOS inhibits Klf2 expression and promotes nuclear localization of NFAT2 (a known driver of CXCR5 expression) in Treg-lineage cells. ICOS-deficient Tfr loss leads to expanded autoreactive B cells and elevated autoantibody titers. Foxp3-Cre × ICOS-flox conditional knockout; single-cell transcriptome analysis; NFAT2 nuclear localization assay; GC B-cell and autoantibody analysis Life science alliance High 36754569
2021 The E3 ubiquitin ligase Peli1 inhibits ICOS expression by limiting c-Rel-mediated transcriptional activation of ICOS. Peli1 deficiency increases ICOS expression on CD4+ T cells, which enhances PI3K-AKT signaling and suppresses Klf2, thereby promoting Tfh differentiation and GC reactions. Peli1 knockout mice; mixed bone marrow chimera; c-Rel signaling analysis; PI3K-AKT activation assays; Klf2 reconstitution experiments; Tfh/GC quantification Cellular & molecular immunology High 33707688
2019 ICOS costimulation is required for the efficacy of combined CTLA-4 + PD-1 blockade in adoptive T-cell therapy; deletion of ICOS in PMEL-1 CD8+ T cells abolishes therapeutic benefit, with selective downregulation of Eomesodermin (Eomes), IFN-γ, and perforin in ICOS-deficient T cells. ICOS-/- PMEL-1 transgenic T-cell adoptive transfer; dual checkpoint blockade; tumor growth assays; intracellular cytokine staining; Eomes expression analysis Cancer immunology research Medium 31466995
2025 Sustained ICOS costimulation limits CD8+ T cell responses during chronic antigen exposure: intrinsic ICOS deficiency increases number and quality of virus-specific CD8+ T cells, potentiates FoxO1 transcription factor activity, and promotes memory-like features of progenitor exhausted (Tpex) cells. ICOS-deficient Tpex cells generate effector-like cells with improved survival and cytokine production. ICOSL blockade expands effector-like PD-1+CD8+ T cells, reduces viral load, and improves response to PD-1 blockade. ICOS-/- mice; chronic LCMV infection; FoxO1 activity assays; single-cell analysis; ICOSL blockade; hepatocellular carcinoma mouse model; PD-1 blockade combination Immunity High 40628269
2022 ICOS/ICOSL interaction between T cells and immunofibroblasts (which upregulate ICOSL during inflammation) induces LTα3 production in ICOS+ T cells, which in turn drives chemokine production required for tertiary lymphoid structure (TLS) assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOSL abrogates LTα expression and TLS formation. ICOS/ICOSL genetic blockade and pharmacological inhibition; immunofibroblast-T cell co-culture; LTα3 production assay; TLS formation readout in mice and humans Communications biology Medium 35508704

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 1163 9930702
2011 ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 793 21636296
2001 ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 707 11343121
1999 T-cell co-stimulation through B7RP-1 and ICOS. Nature 615 10617205
2001 ICOS is essential for effective T-helper-cell responses. Nature 515 11343123
2018 Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI insight 469 29321369
2013 Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility. Nature 328 23619696
2014 ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 286 24986688
2003 Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nature reviews. Immunology 286 12876557
2015 ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity. Immunity 257 25769613
2015 ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2. The Journal of experimental medicine 250 25646266
2016 ICOS Co-Stimulation: Friend or Foe? Frontiers in immunology 237 27559335
2010 Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS). Current opinion in immunology 177 20116985
2015 Agonists of Co-stimulation in Cancer Immunotherapy Directed Against CD137, OX40, GITR, CD27, CD28, and ICOS. Seminars in oncology 168 26320067
2000 Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand. European journal of immunology 154 10760791
2000 Inducible costimulator protein (ICOS) controls T helper cell subset polarization after virus and parasite infection. The Journal of experimental medicine 150 10880526
2020 The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy. ESMO open 134 32516116
2020 ICOS+ Tregs: A Functional Subset of Tregs in Immune Diseases. Frontiers in immunology 134 32983168
2009 Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS. Immunity 119 19217324
2003 The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity. The Journal of clinical investigation 116 12865411
2020 ICOS Is an Indicator of T-cell-Mediated Response to Cancer Immunotherapy. Cancer research 97 32156777
2013 ICOS controls Foxp3(+) regulatory T-cell expansion, maintenance and IL-10 production during helminth infection. European journal of immunology 96 23319295
2019 Role of Inducible Co-Stimulator (ICOS) in cancer immunotherapy. Expert opinion on biological therapy 94 31738626
2021 Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8+ tissue-resident memory T cells. Immunity 87 34932944
2001 ICOS costimulation requires IL-2 and can be prevented by CTLA-4 engagement. Journal of immunology (Baltimore, Md. : 1950) 87 11290772
2008 ICOS/ICOSL interaction is required for CD4+ invariant NKT cell function and homeostatic survival. Journal of immunology (Baltimore, Md. : 1950) 74 18390727
2018 Inducible Co-Stimulator (ICOS) as a potential therapeutic target for anti-cancer therapy. Expert opinion on therapeutic targets 69 29468927
2022 PD-1 and ICOS coexpression identifies tumor-reactive CD4+ T cells in human solid tumors. The Journal of clinical investigation 68 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 68 33087332
2009 The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency. Immunological reviews 68 19426217
2022 First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response. Clinical cancer research : an official journal of the American Association for Cancer Research 57 35511938
2006 CD28 and ICOS: similar or separate costimulators of T cells? Immunology letters 57 16580736
2018 ICOS-L as a Potential Therapeutic Target for Cancer Immunotherapy. Current protein & peptide science 56 29879883
2015 IL-6 and ICOS Antagonize Bim and Promote Regulatory T Cell Accrual with Age. Journal of immunology (Baltimore, Md. : 1950) 53 26109645
2021 Vaccine-induced ICOS+CD38+ circulating Tfh are sensitive biosensors of age-related changes in inflammatory pathways. Cell reports. Medicine 48 34095875
2007 Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice. Clinical immunology (Orlando, Fla.) 47 17889619
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 46 37086778
2005 Renal tubular epithelial cells modulate T-cell responses via ICOS-L and B7-H1. Kidney international 46 16221208
2011 CTLA-4, CD28, and ICOS gene polymorphism associations with non-small-cell lung cancer. Human immunology 44 21669243
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
2020 Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies. Nature communications 42 33033255
2016 IL2 Variant Circumvents ICOS+ Regulatory T-cell Expansion and Promotes NK Cell Activation. Cancer immunology research 42 27697858
2003 PI3-kinase and MAP-kinase signaling cascades in AILIM/ICOS- and CD28-costimulated T-cells have distinct functions between cell proliferation and IL-10 production. Biochemical and biophysical research communications 41 14550257
2000 AILIM/ICOS: a novel lymphocyte adhesion molecule. International immunology 38 10607749
2020 An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression. Cancer immunology research 37 32999002
2016 ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Vivo. Journal of immunology (Baltimore, Md. : 1950) 37 27798154
2006 CD28/CTLA-4--CD80/CD86 and ICOS--B7RP-1 costimulatory pathway in bronchial asthma. Allergy 37 16364152
2000 The T cell activation molecule H4 and the CD28-like molecule ICOS are identical. European journal of immunology 37 11093165
2019 Blockade of CTLA-4 and PD-1 Enhances Adoptive T-cell Therapy Efficacy in an ICOS-Mediated Manner. Cancer immunology research 36 31466995
2015 ICOS promotes group 2 innate lymphoid cell activation in lungs. Biochemical and biophysical research communications 36 26049110
2005 ICOS costimulates invariant NKT cell activation. Biochemical and biophysical research communications 36 15629449
2018 CXCR5 and ICOS expression identifies a CD8 T-cell subset with TFH features in Hodgkin lymphomas. Blood advances 35 30087107
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
2000 Identification and characterization of rat AILIM/ICOS, a novel T-cell costimulatory molecule, related to the CD28/CTLA4 family. Biochemical and biophysical research communications 33 11006126
2018 Transmembrane domain-mediated Lck association underlies bystander and costimulatory ICOS signaling. Cellular & molecular immunology 32 30523347
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
2024 ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype. The Journal of experimental medicine 31 38517331
2011 CD10 and ICOS expression by multiparametric flow cytometry in angioimmunoblastic T-cell lymphoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 31 21499231
2003 Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways. European journal of immunology 31 12594849
2021 Distinct roles of ICOS and CD40L in human T-B cell adhesion and antibody production. Cellular immunology 30 34418679
2022 Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction. Communications biology 29 35508704
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
2017 ICOS protects against mortality from acute lung injury through activation of IL-5+ ILC2s. Mucosal immunology 29 28488693
2021 The ubiquitin ligase Peli1 inhibits ICOS and thereby Tfh-mediated immunity. Cellular & molecular immunology 28 33707688
2020 ICOS is widely expressed in cutaneous T-cell lymphoma, and its targeting promotes potent killing of malignant cells. Blood advances 28 33095875
2011 Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS. Blood 28 21765024
2023 Targeting the Inducible T-cell Costimulator (ICOS) in Patients with Relapsed/Refractory T-follicular Helper Phenotype Peripheral T-cell and Angioimmunoblastic T-cell Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research 27 36826995
2023 ICOS and OX40 tandem co-stimulation enhances CAR T-cell cytotoxicity and promotes T-cell persistence phenotype. Frontiers in oncology 27 37719008
2021 ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue. The Journal of experimental medicine 27 33881452
2018 ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis. Journal of immunology (Baltimore, Md. : 1950) 27 29581356
2001 AILIM/ICOS: its expression and functional analysis with monoclonal antibodies. Hybridoma and hybridomics 26 11839247
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
2019 Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency. Journal of clinical immunology 24 31858365
2015 Downregulation of myeloma-induced ICOS-L and regulatory T cell generation by lenalidomide and dexamethasone therapy. Cellular immunology 22 26051632
2004 ICOS: a new costimulatory ligand/receptor pair and its role in T-cell activion. Onkologie 22 15007255
2022 Acazicolcept (ALPN-101), a dual ICOS/CD28 antagonist, demonstrates efficacy in systemic sclerosis preclinical mouse models. Arthritis research & therapy 21 34986869
2019 ICOS deficiency hampers the homeostasis, development and function of NK cells. PloS one 20 31283790
2024 Discovery of ICOS-Targeted Small Molecules Using Affinity Selection Mass Spectrometry Screening. ChemMedChem 19 39269728
2012 Augmented ICOS expression in patients with early diffuse cutaneous systemic sclerosis. Rheumatology (Oxford, England) 19 23024058
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
2019 High CD3 and ICOS and low TIM-3 expression predict favourable survival in resected oesophageal squamous cell carcinoma. Scientific reports 17 31882943
2019 T cell Co-Stimulatory molecules ICOS and CD28 stratify idiopathic pulmonary fibrosis survival. Respiratory medicine: X 17 32455343
2023 ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells. Life science alliance 16 36754569
2019 IL-10 and ICOS Differentially Regulate T Cell Responses in the Brain during Chronic Toxoplasma gondii Infection. Journal of immunology (Baltimore, Md. : 1950) 16 30718297
2019 T Cell-Intrinsic IL-6R Signaling Is Required for Optimal ICOS Expression and Viral Control during Chronic Infection. Journal of immunology (Baltimore, Md. : 1950) 16 31413107
2023 Discovery of ICOS-Targeted Small Molecules Using Pharmacophore-Based Screening. ChemMedChem 15 37845178
2020 ICOS signaling promotes a secondary humoral response after re-challenge with Plasmodium chabaudi chabaudi AS. PLoS pathogens 15 32348365
2023 First-in-class small molecule inhibitors of ICOS/ICOSL interaction as a novel class of immunomodulators. RSC medicinal chemistry 14 37731692
2021 ICOS ligand and IL-10 synergize to promote host-microbiota mutualism. Proceedings of the National Academy of Sciences of the United States of America 14 33753483
2018 ICOS Costimulation Differentially Affects T Cells in Secondary Lymphoid Organs and Inflamed Tissues. American journal of respiratory cell and molecular biology 14 29676593
2010 Biased binding of class IA phosphatidyl inositol 3-kinase subunits to inducible costimulator (CD278). Cellular and molecular life sciences : CMLS 14 21188463
2008 Suppression of T cell costimulator ICOS by Delta9-tetrahydrocannabinol. Journal of leukocyte biology 14 18988696
2006 AILIM/ICOS-mediated elongation of activated T cells is regulated by both the PI3-kinase/Akt and Rho family cascade. International immunology 14 17077177
2025 CD28 and ICOS in immune regulation: Structural insights and therapeutic targeting. Bioorganic & medicinal chemistry letters 13 40527414
2025 The costimulatory molecule ICOS limits memory-like properties and function of exhausted PD-1+CD8+ T cells. Immunity 13 40628269

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