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Showing ICOSLG — ICOSL is a alias.

ICOSLG

ICOS ligand · UniProt O75144

Length
302 aa
Mass
33.3 kDa
Annotated
2026-06-10
54 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ICOSLG (B7RP-1/B7-H2/GL50/CD275) is a B7-family transmembrane costimulatory ligand that engages the ICOS receptor on activated T cells to license T-cell-dependent humoral immunity, mucosal tolerance, and inflammatory responses across both hematopoietic and epithelial tissues (PMID:10617205, PMID:11023515, PMID:12714510). First identified as a CD28/CTLA-4-independent ICOS ligand expressed on B cells, dendritic cells, and macrophages, it costimulates T-cell proliferation and cytokine output and binds ICOS with ~33 nM affinity and a long off-rate (PMID:10617205, PMID:10657606, PMID:11007762). Genetically, ICOSLG is required for germinal center formation, antibody class-switching, recall responses, and Th2 cytokine production, and for the maintenance of follicular helper T cells and germinal center B cells in autoimmune settings (PMID:12714510, PMID:19155489). Beyond its canonical ICOS interaction, human ICOSLG additionally serves as a ligand for CD28 and CTLA-4 through distinct domains—interactions absent in mouse—driving ERK/AKT-dependent costimulation, Bcl-xL induction, and p27kip1 downregulation in human T cells (PMID:21530327). ICOSLG is constitutively expressed on diverse epithelia (renal tubular, airway, alveolar, smooth muscle), where the pathway can negatively regulate local T-cell activation, and is essential for inhalation tolerance at mucosal surfaces (PMID:12039981, PMID:12707012, PMID:15728513, PMID:16552709). ICOSLG also acts cell-intrinsically as a signaling receptor: its cytoplasmic tail uses arginine residues to recruit RACK1 and the kinases PKC and JNK, amplifying PRR/NOD2-initiated NF-κB-dependent cytokine secretion, a function impaired by a Crohn's disease risk allele (PMID:24837102). Its surface expression is dynamically controlled by inflammatory cues, including MyD88-dependent TLR signaling (antagonized by type I IFN) and TNF-α/NF-κB induction, and transcriptionally by RUNX1-directed recruitment of the acetyltransferase GCN5 to the ICOSLG promoter in psoriatic keratinocytes, where ICOSLG-ICOS signaling drives keratinocyte-dependent T-cell activation (PMID:15884053, PMID:16552709, PMID:42243529). In tumors, ICOSLG induced via TNF-α/NF-κB expands IL-10-producing regulatory T cells and dampens cytotoxic responses, and supports a glycolysis-dependent oncogenic phenotype in gastric cancer (PMID:31634400, PMID:34185422, PMID:38081339). Autosomal recessive loss-of-function mutations in ICOSLG cause a combined immunodeficiency with susceptibility to DNA viruses at epithelial barriers (PMID:33756276).

Mechanistic history

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

    Established the molecular identity of ICOSLG by showing it is the dedicated ligand for the ICOS receptor that costimulates T cells independently of the CD28/CTLA-4 axis, defining a new B7-family costimulatory pathway.

    Evidence Receptor-ligand binding and T cell costimulation assays plus B7RP-1-Fc transgenic mice

    PMID:10617205

    Open questions at the time
    • Downstream signaling and tissue-specific roles not yet defined
    • Human ortholog function not addressed
  2. 2000 High

    Confirmed the human ligand (B7-H2/GL50) binds activated T cells via ICOS but not CTLA-4/CD28, quantified the binding affinity, and showed it preferentially drives IL-10 and other cytokines, framing it as a tunable costimulator.

    Evidence Competition binding (ICOS-Ig vs CTLA4-Ig/CD28-Ig), CHO transfectants, T cell cytokine assays, and binding kinetics (KD ~33 nM)

    PMID:10657606 PMID:11007762 PMID:11023515

    Open questions at the time
    • In vivo physiological roles not yet tested
    • Cytoplasmic signaling not characterized
  3. 2003 High

    Placed ICOSLG in the humoral immunity pathway by showing knockout mice fail to form germinal centers, class-switch antibodies, and produce Th2 cytokines, with the defect mapping to T cell help rather than intrinsic B cell function.

    Evidence Gene-targeted B7-H2 knockout mice, T-dependent/independent immunization, antibody and cytokine ELISA, in vitro B cell stimulation

    PMID:12714510 PMID:12853164

    Open questions at the time
    • Molecular signaling driving Th2 skewing not resolved
    • Role of epithelial vs hematopoietic ICOSLG not separated
  4. 2004 Medium

    Revealed that ICOSLG is constitutively expressed on diverse epithelia and can act as a negative regulator of local T-cell activation, indicating context-dependent (costimulatory vs inhibitory) outputs.

    Evidence Expression profiling (flow, WB, IHC) of renal tubular and airway epithelial cells plus blocking-antibody T cell hybridoma assays

    PMID:12039981 PMID:12707012 PMID:14527172 PMID:15361696

    Open questions at the time
    • Mechanism converting costimulation to inhibition unknown
    • No genetic confirmation of the epithelial inhibitory role
  5. 2005 Medium

    Defined how ICOSLG surface expression is controlled by innate signaling—MyD88-dependent TLR induction counterbalanced by TRIF/type I IFN suppression—linking pathogen sensing to costimulator availability.

    Evidence LPS stimulation of TRIF-/-, TRAM-/-, MyD88-/- macrophages/B cells with recombinant type I IFN, flow cytometry

    PMID:15884053

    Open questions at the time
    • Transcription factors directly driving ICOSLG induction not identified
    • Human relevance not tested
  6. 2005 Medium

    Distinguished redundant from essential ICOSLG functions at mucosal surfaces, showing it is dispensable for Th2 generation but non-redundant for inhalation tolerance.

    Evidence B7RP-1 knockout mice in aerosol OVA sensitization/tolerance models with cytokine, eosinophil, and antibody readouts

    PMID:15728513

    Open questions at the time
    • Cellular mediator of tolerance (Treg vs other) not pinned down
    • Mechanism distinct from sensitization unexplained
  7. 2009 Medium

    Extended the humoral role by showing ICOSLG signaling maintains follicular helper T cells and germinal center B cells, and that blockade ameliorates autoimmune disease.

    Evidence Anti-B7RP-1 mAb in lupus and arthritis mouse models with TFH/GC flow cytometry and B cell cocultures

    PMID:19155489

    Open questions at the time
    • Direct effect on B cell IgG production not observed, leaving mechanism indirect
    • Single lab
  8. 2011 High

    Discovered that human ICOSLG is also a ligand for CD28 and CTLA-4 through distinct domains—an interaction not conserved in mouse—coupling it to ERK/AKT signaling, Bcl-xL induction, and p27kip1 downregulation in human T cells.

    Evidence Receptor array, domain mapping, human allogeneic T cell assays, western blots, and human/mouse species comparison

    PMID:21530327

    Open questions at the time
    • Relative in vivo contribution of CD28 vs ICOS engagement in humans unresolved
    • Structural basis of domain-specific binding not defined here
  9. 2014 High

    Showed ICOSLG functions bidirectionally as a signaling receptor: its cytoplasmic arginine residues recruit RACK1, PKC, and JNK to amplify NOD2/PRR-driven NF-κB cytokine output, with a Crohn's risk allele reducing this signaling.

    Evidence Cytoplasmic tail mutagenesis, RACK1 Co-IP, PKC/JNK kinase and NF-κB assays, NOD2 stimulation, and human risk-allele MDDC assays

    PMID:24837102

    Open questions at the time
    • Whether reverse signaling operates in epithelial as well as dendritic cells unknown
    • Structural detail of RACK1 docking not resolved
  10. 2023 Medium

    Defined a tumor-promoting axis whereby inflammatory cues (TNF-α/NF-κB, ERK) induce ICOSLG on tumor cells and neutrophils to expand IL-10/IL-17-producing T cells, suppress cytotoxicity, and support glycolysis-dependent growth.

    Evidence TNF-α/NF-κB pathway analysis, ICOSLG knockdown/overexpression, T cell cocultures, glycolysis assays, miR-331-3p targeting, and in vivo tumor models

    PMID:21958057 PMID:22732700 PMID:31634400 PMID:34185422 PMID:38081339

    Open questions at the time
    • Direct molecular link between ICOSLG and glycolytic machinery not mechanistically resolved
    • Some tumor findings rest on single blocking/knockdown approaches
  11. 2021 Medium

    Provided the human in vivo loss-of-function evidence: biallelic ICOSLG mutations cause combined immunodeficiency with epithelial-barrier susceptibility to DNA viruses, confirming the ICOSL:ICOS axis is essential for mucocutaneous immunity.

    Evidence Human genetic study of ICOSLG-deficient patients with clinical phenotyping versus ICOS-deficient patients

    PMID:33756276

    Open questions at the time
    • No biochemical reconstitution of mutant alleles
    • Synthesized from clinical genetics rather than direct mechanism
  12. 2026 High

    Identified the transcriptional control of ICOSLG in disease tissue, showing RUNX1 recruits the acetyltransferase GCN5 to the ICOSLG promoter in psoriatic keratinocytes to drive ICOSLG-ICOS-mediated T cell activation and lesion formation.

    Evidence scRNA-seq, multiplex IHC colocalization, chromatin/ChIP assays of RUNX1-GCN5 at the promoter, keratinocyte-specific GCN5 knockout mice, and the GCN5 inhibitor MB-3 in an imiquimod psoriasis model

    PMID:42243529

    Open questions at the time
    • Whether RUNX1-GCN5 control of ICOSLG operates beyond keratinocytes unknown
    • Direct RUNX1-promoter contact resolution not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ICOSLG integrates its dual roles—as a forward costimulatory ligand (for ICOS, and in humans CD28/CTLA-4) and as a reverse-signaling receptor recruiting RACK1—to produce either costimulatory or inhibitory outputs in a given tissue remains unresolved.
  • No structural model integrating the distinct receptor-binding domains
  • Determinants selecting costimulation vs inhibition on epithelia not defined
  • In vivo contribution of reverse signaling vs ligand function not separated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 2 GO:0060089 molecular transducer activity 1 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 2
Partners
CD28CTLA4ICOSKAT2AMAPK8PRKCRACK1RUNX1

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 B7RP-1 (ICOSLG) was identified as the ligand for the ICOS receptor (murine homologue). B7RP-1 is expressed on B cells and macrophages, does not interact with CD28 or CTLA-4, and co-stimulates T cell proliferation in vitro independently of CD28. A B7RP-1-Fc fusion protein caused lymphoid hyperplasia in transgenic mice and enhanced hypersensitivity in presensitized mice. Receptor-ligand binding assays, T cell co-stimulation assays in vitro, transgenic mouse models expressing B7RP-1-Fc fusion protein Nature High 10617205
2000 Human B7-H2 (ICOSLG) protein is expressed on monocyte-derived immature dendritic cells. Soluble B7-H2-Ig fusion protein binds activated but not resting T cells; this binding is abrogated by ICOS-Ig but not CTLA4-Ig, establishing B7-H2 as a ligand for ICOS. B7-H2 co-stimulates T cell proliferation and IL-2 secretion under suboptimal CD3 ligation, and preferentially stimulates IL-10 production under optimal CD3 ligation. Flow cytometry (B7-H2-Ig binding to T cells), competition binding with ICOS-Ig and CTLA4-Ig, CHO cell transfection with ICOS staining, T cell proliferation and cytokine secretion assays Blood High 11023515
2000 Mouse GL50 (mGL50) and human GL50 (hGL50) are ICOS-specific ligands. Of CD28-Ig, CTLA4-Ig, and ICOS-Ig fusion proteins tested, only ICOS-IgG bound to mGL50-transfected cells. High ICOS ligand staining was found on splenic CD19+ B cells and low levels on CD3+ T cells. Genetic selection of secreted mouse cDNAs, flow cytometric binding analysis of ICOS-Ig vs CD28-Ig/CTLA4-Ig on cell transfectants, Northern analysis, RT-PCR Journal of immunology High 10657606
2000 Human B7RP-1 (ICOSLG) binds ICOS with a KD of approximately 33 nM and a long off-rate (t1/2 > 10 min). TNF-α differentially regulates human B7RP-1 expression: enhancing it on B cells and monocytes while inhibiting it on dendritic cells. B7RP-1 co-stimulates T cell proliferation and induces IFN-γ and IL-10 (but not significantly IL-2), and B7RP-1 co-stimulation is dependent on IL-2. Binding kinetics assays (KD and off-rate measurements), flow cytometry for expression regulation, T cell co-stimulation and cytokine assays International immunology High 11007762
2001 Mouse GL50 has an alternatively spliced form (mGL50-B) with a divergent 27-aa intracellular domain. Both mGL50 and mGL50-B transfected cells bind ICOS-Ig, demonstrating that the alternate cytoplasmic domain does not affect extracellular ICOS interaction. Both splice variants are expressed in B cells, T cells, macrophages, and dendritic cells. Differential splicing at the cytoplasmic exon 6/7 junction is a conserved regulatory mechanism also observed for human hGL50/B7-H2. 3'RACE to identify splice variants, ICOS-Ig fusion protein binding to transfected cells by flow cytometry, RT-PCR and flow cytometric analysis of mouse splenocyte subsets Journal of immunology Medium 11390480
2001 ICOS-B7RP-1 costimulation is required for acute and chronic allograft rejection. Anti-ICOS antibody and ICOS-Ig fusion protein (which blocks B7RP-1-ICOS interaction) suppressed intragraft T cell activation and cytokine expression and prolonged allograft survival similar to ICOS-/- mice. ICOS-B7RP-1 costimulation was required for chronic rejection occurring after CD40-CD154 blockade. Mouse allograft transplantation model, anti-ICOS mAb and ICOS-Ig blockade, genetic knockout (ICOS-/- mice), intragraft cytokine analysis Nature immunology High 11429542
2002 B7RP-1 (ICOSLG) is constitutively and abundantly expressed on renal tubular epithelial cells (TEC) in vitro and in vivo (distal tubules, collecting ducts, urothelium), whereas B7.1 and B7.2 are not detectable. Blocking antibodies to B7RP-1 or ICOS enhanced IL-2 production by T cell hybridomas during antigen presentation by TEC, indicating that the B7RP-1/ICOS pathway negatively regulates T cell activation in this context. Immunostaining and flow cytometry for B7RP-1 expression on TEC lines and human kidney sections, functional T cell hybridoma assays with blocking antibodies Journal of the American Society of Nephrology Medium 12039981
2003 B7-H2 (ICOSLG) knockout mice generate normal B and T cell populations but show impaired germinal center formation, reduced heavy-chain class-switched antibodies (both basal and antigen-specific), defective recall antibody responses to T-dependent antigens, and reduced Th2 cytokines (IL-4, IL-10) from primed CD4+ T cells. B cells from knockout mice responded normally to anti-IgM, anti-CD40, and LPS, indicating the defect is T cell-mediated. Gene-targeted B7-H2 knockout mice, immunization with T-dependent and T-independent antigens, ELISA for antibody titers and cytokines, germinal center analysis Blood High 12714510
2003 Blockade of ICOS-B7RP-1 costimulation with anti-ICOS mAb in murine schistosomiasis enhanced hepatic immunopathology (enlarged granulomas, hepatocellular necrosis, elevated liver enzymes) and sharply increased IFN-γ production by CD4+ T cells, while Th2 cytokines (IL-4, IL-10) were only modestly affected. This demonstrates that the ICOS-B7RP-1 pathway primarily controls IFN-γ production and promotes a cytokine environment limiting hepatic damage. Anti-ICOS mAb blockade in murine schistosomiasis model, cytokine assays on granuloma cells and lymph node CD4+ T cells, liver enzyme measurements, histopathology Infection and immunity Medium 12819093
2003 B7RP-1/ICOS pathway negatively regulates T cell activation during antigen presentation by B cells. Blocking antibodies for B7RP-1 or ICOS enhanced IL-2 production by T cell hybridomas, IFN-γ by Th1 cells, and IL-4 by Th2 cells in a B cell antigen presentation assay, demonstrating an inhibitory role analogous to PD-L1/PD-1. T cell hybridoma activation assays with CH27 B cells and blocking antibodies (anti-B7RP-1, anti-ICOS, anti-PD-1), intracellular cytokine staining Inflammation Medium 14527172
2003 B7-H2 (ICOSLG) is constitutively expressed on human airway epithelial cells (BEAS-2B cell line and primary bronchial epithelial cells) but not B7-1 or B7-2. Expression was confirmed by flow cytometry, Western blot, Northern blot, and RT-PCR. Various cytokines (TNF-α, IFN-γ, IL-4) slightly downregulated surface B7-H2 without significant protein-level change by Western blot. B7-H2 expression was confirmed by immunohistochemistry in human airway tissue. Flow cytometry, Western blot, Northern blot, RT-PCR, immunohistochemistry on airway epithelial cells and tissue sections American journal of respiratory cell and molecular biology Medium 12707012
2003 ICOS/B7RP-1 interactions are required for functional germinal center formation in Peyer's patches. ICOS-/- mice had significantly reduced Peyer's patch size, complete absence of PNA+ germinal center cells, and significantly reduced IgA and IgG (but not IgM) production in Peyer's patches, demonstrating a requirement for this costimulatory pathway in T-dependent B cell help at mucosal sites. ICOS-/- mice, phenotypic analysis of Peyer's patches by flow cytometry, peanut agglutinin staining for germinal centers, ELISA for immunoglobulin isotypes Immunology letters Medium 12853164
2003 Soluble B7RP-1-Fc causes rejection or growth inhibition of syngeneic tumors (Meth A, SA-1, EMT6) in mice. Single-dose treatment was sufficient to reject established Meth A tumors, and mice that rejected tumors showed long-lived memory (resisting rechallenge on day 60 without additional treatment). The mechanism involves targeting T cells. Syngeneic tumor models in mice, B7RP-1-Fc treatment, tumor rejection and rechallenge assays International journal of cancer Medium 12478666
2004 The B7RP-1/ICOS pathway inhibits Th1 and Th2 T cell responses during antigen presentation by renal tubular epithelial cells. Blockade of B7RP-1/ICOS with mAbs further increased IFN-γ production by Th1 cells and IL-4 production by Th2 cells, and protein arrays showed increased Th2 cytokine levels upon blockade, supporting a negative-feedback inhibitory role for this pathway in tubulointerstital immunity. IFN-γ-stimulated murine primary TEC antigen presentation assays, gene arrays, ELISA, protein arrays with B7RP-1/ICOS blocking mAbs Nephron. Experimental nephrology Medium 15361696
2005 LPS-induced up-regulation of B7RP-1 (ICOSLG) is dependent primarily on the MyD88-dependent TLR signaling pathway, not the TRIF pathway. Conversely, TRIF-dependent signaling (via Type I IFN) sharply limits MyD88-dependent B7RP-1 upregulation. Type I IFNs were found to be general suppressors of TLR-mediated B7RP-1 upregulation, revealing a dual regulatory mechanism for B7 costimulatory family expression. LPS stimulation of TRIF-/-, TRAM-/-, and MyD88-/- mouse peritoneal macrophages and splenic B cells, flow cytometry for B7RP-1 expression, recombinant Type I IFN treatment European journal of immunology Medium 15884053
2005 B7RP-1 knockout mice can mount Th2 responses (airway eosinophilia, Th2 cytokines IL-5/IL-4/IL-13, IgE/IgG1) in a model of mucosal allergic sensitization, indicating B7RP-1 is redundant for Th2 generation in this context. However, B7RP-1 knockout mice are resistant to inhalation tolerance induction, demonstrating an essential and non-redundant role for ICOSLG in peripheral tolerance at mucosal surfaces. B7RP-1 knockout mice, aerosolized OVA/GM-CSF sensitization model, airway eosinophil counts, cytokine and antibody ELISA, T cell surface marker analysis Journal of immunology Medium 15728513
2006 Human type II alveolar epithelial cells (A549 line) constitutively express B7-H2 (ICOSLG), and TNF-α significantly induces B7-H2 expression. Co-culture of TNF-α-prestimulated A549 cells with CD4+ T cells promoted CD154 expression, CD4+ T cell proliferation, and IFN-γ production. TNF-α-deficient mice show reduced B7-H2 on alveolar epithelial cells compared to wild-type. Blockade of B7H2 in co-culture inhibited IFN-γ production. Flow cytometry, co-culture of A549 cells with CD4+ T cells, cytokine ELISA, TNF-α knockout mice for in vivo B7-H2 expression analysis, antibody blocking experiments European journal of immunology Medium 16552709
2009 ICOS/B7RP-1 signaling is required for the maintenance of follicular helper T cells (TFH) and germinal center B cells in autoimmune mouse models (NZB/NZW F1 lupus and collagen-induced arthritis). Anti-B7RP-1 antibody treatment reduced TFH cells, GC B cells, and overall ICOS+ T cell frequency, and ameliorated disease. B7RP-1 blockade did not directly impair IgG production by B cells in coculture with antigen-primed B cells and CXCR5+ T cells. Anti-B7RP-1 mAb treatment in two autoimmune mouse models, flow cytometry for TFH and GC B cells, CXCR5+/- T cell coculture with B cells and IgG ELISA Journal of immunology Medium 19155489
2009 B7-H2 (ICOSLG) expressed on human airway smooth muscle (ASM) cells mediates adhesion of ICOS-expressing activated T cells. Engagement of B7-H2 with ICOS-Ig on ASM cells induces DNA synthesis (cell proliferation) but not IL-6/IL-8 production, distinguishing its signaling from CD40 and OX40L on the same cells. Poly I:C upregulates B7-H2 expression on ASM cells and enhances T cell adhesion. RT-PCR and flow cytometry for expression, T cell-ASM adhesion assays, ICOS-Ig engagement of B7-H2 on ASM cells, DNA synthesis assay, cytokine ELISA, poly I:C stimulation Allergology international Medium 19776675
2011 B7-H2 (ICOSLG) is a ligand for human CD28 and CTLA-4 in addition to ICOS; these interactions are not conserved in mouse. B7-H2 and B7-1/B7-2 interact with CD28 through distinctive domains. B7-H2-CD28 interaction is essential for costimulation of human T cells' primary allogeneic responses and memory recall responses, and induces Bcl-xL, downregulates p27(kip1), and triggers ERK and AKT kinase-dependent signaling. Receptor array assay identifying B7-H2 binding to CD28 and CTLA-4, domain mapping, human T cell allogeneic stimulation assays, western blot for Bcl-xL/p27(kip1)/ERK/AKT, species comparison (human vs. mouse) Immunity High 21530327
2013 H. pylori CagA protein downregulates B7-H2 (ICOSLG) expression on gastric epithelial cells (GECs) in a CagA-dependent manner, involving p70 S6 kinase phosphorylation. IFN-γ synergizes with H. pylori in this downregulation. CagA-mediated B7-H2 downregulation correlates with decreased Th17 responses in vitro and in vivo, and inversely correlates with H. pylori colonization levels. H. pylori infection of GEC lines with isogenic CagA-mutant strains, flow cytometry and ELISA for B7-H2 expression, p70 S6K phosphorylation assay, in vitro Th17 cytokine assays, in vivo mouse infection model Journal of immunology Medium 23997227
2014 ICOS ligand (ICOSL/ICOSLG) on monocyte-derived dendritic cells amplifies NOD2-initiated cytokine secretion through homotypic ICOS-ICOSL interactions. This amplification requires arginine residues in the ICOSL cytoplasmic tail, which recruit the adaptor protein RACK1 and the kinases PKC and JNK, leading to PKC, MAPK, and NF-κB activation. The Crohn's disease ICOSLG risk allele (rs7282490 GG) reduces ICOSL expression and PRR-initiated signaling. Cytoplasmic tail mutagenesis (arginine residue mutation), co-immunoprecipitation for RACK1 binding, kinase activity assays (PKC, JNK), NF-κB activation assays, MDDC cytokine assays from risk vs. non-risk allele carriers, NOD2 stimulation Immunity High 24837102
2020 ICOSLG expression in mesenchymal glioblastoma sphere cells (GSCs) is upregulated by TNF-α in an NF-κB-dependent manner. ICOSLG expression by mesenchymal GSCs promotes expansion of IL-10-producing T cells (regulatory T cells). Knockdown of ICOSLG markedly reduced GBM tumor growth in immunocompetent mice with concomitant downregulation of IL-10 in the tumor microenvironment. TNF-α stimulation of patient-derived GSCs with NF-κB pathway analysis, ICOSLG knockdown (siRNA/shRNA), T cell co-culture and IL-10 measurement, in vivo tumor growth assays in immunocompetent mice Neuro-oncology Medium 31634400
2021 TNF-α-activated neutrophils in gastric cancer express B7-H2 (ICOSLG) through TNF-α-ERK-NF-κB signaling. Tumor-derived TNF-α promotes neutrophil B7-H2 expression in dose- and time-dependent manners. B7-H2+ neutrophils induce IL-17A-producing Th cell polarization in a B7-H2-dependent manner ex vivo, and these Th cells promote tumor cell proliferation in vitro and GC progression in vivo; blocking IL-17A reversed these effects. Flow cytometry and IHC for B7-H2+ neutrophils, ERK-NF-κB pathway inhibition assays, ex vivo T cell polarization with B7-H2 blocking antibody, in vitro tumor cell proliferation assay, in vivo mouse tumor model with IL-17A blockade Clinical and translational medicine Medium 34185422
2021 Autosomal recessive loss-of-function mutations in ICOSLG result in combined immunodeficiency in humans, characterized by recurrent respiratory tract infections and susceptibility to DNA-based viruses (including HPV) at epithelial barriers, revealing a critical role for ICOSL:ICOS axis in mucocutaneous immunity. Human genetic study of ICOSLG-deficient patients (loss-of-function mutations identified), clinical phenotype characterization with comparison to ICOS-deficient patients Current opinion in immunology Medium 33756276
2023 miR-331-3p negatively regulates ICOSLG expression in gastric cancer cells. ICOSLG knockdown inhibited proliferation, migration, invasion, tumor formation, and glycolysis (glucose consumption, lactate production, ATP levels) of GC cells in vitro and in vivo. ICOSLG overexpression enhanced aggressiveness, and this was abrogated by glycolysis inhibitor treatment, demonstrating a glycolysis-dependent oncogenic mechanism. miRDB/starBase/TargetScan prediction followed by functional validation, CCK-8 proliferation assay, Transwell migration/invasion assays, glucose uptake/lactate/ATP assays, xenograft tumor model in nude mice, glycolysis inhibitor treatment Archives of biochemistry and biophysics Medium 38081339
2012 ICOSLG expressed on mouse hematological neoplasm cells (FBL3, A20, P388) suppresses cytotoxic alloreactive T cell activity. ICOSLG blockade enhanced cytotoxicity at E:T ratios of 20:1–30:1 and was associated with decreased IL-4 and IL-10 expression, indicating ICOSLG on tumor cells dampens cytotoxic immune responses via Th2 cytokine induction. Flow cytometry for ICOSLG expression on cell lines, alloreactive cytotoxicity assays at varied E:T ratios, ICOSLG-blocking antibody, ELISA for IL-4 and IL-10 Leukemia & lymphoma Low 21958057
2012 ICOSLG knockdown in A20 mouse leukemia cells significantly enhanced graft-versus-leukemia (GVL) effect after allogeneic bone marrow transplantation, delaying mortality compared to controls, demonstrating that tumor cell ICOSLG suppresses anti-tumor GVL immune responses. ICOSLG gene silencing (RNA interference) in A20 leukemia cells, allogeneic BMT mouse GVL model, survival analysis Bone marrow transplantation Low 22732700
2010 ICOS-B7H2 (ICOSLG) interactions at the human fetomaternal interface regulate T cell cytokine production. Decidual T cells express high ICOS, especially on CD45RO+ cells and CD4+Foxp3+ regulatory T cells. ICOS ligation enhanced IFN-γ and IL-10 but not IL-2 secretion, with greater effect on decidual than peripheral T cells. Co-culture of T cells with trophoblast (JEG3) cells enhanced IFN-γ and IL-10, blocked by anti-MHC class I or anti-B7H2 antibodies. Flow cytometry for ICOS expression on decidual and peripheral T cells, ICOS ligation assay, JEG3 trophoblast co-culture with antibody blocking, cytokine ELISA Immunology and cell biology Medium 20733594
2026 In psoriatic keratinocytes, RUNX1 transcriptionally upregulates ICOSLG expression by recruiting the histone acetyltransferase GCN5 to the ICOSLG promoter. The GCN5 inhibitor MB-3 reduces ICOSLG expression in keratinocytes. ICOSLG-ICOS signaling between keratinocytes and T cells (confirmed by colocalization of ICOSLG and ICOS in psoriasis lesions) mediates keratinocyte-dependent T cell activation. In a mouse psoriasis model, MB-3 treatment and keratinocyte-specific GCN5 knockdown reduced ICOSLG expression and T cell activation and ameliorated psoriatic lesions. Single-cell RNA sequencing, multiplex immunohistochemistry (ICOSLG-ICOS colocalization), ChIP-seq/chromatin assay for RUNX1-GCN5 at ICOSLG promoter, keratinocyte-specific GCN5 knockout mice, imiquimod psoriasis model, GCN5 inhibitor MB-3 treatment Experimental & molecular medicine High 42243529

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 T-cell co-stimulation through B7RP-1 and ICOS. Nature 615 10617205
2001 Importance of ICOS-B7RP-1 costimulation in acute and chronic allograft rejection. Nature immunology 249 11429542
2000 Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS. Blood 212 11023515
2000 Cutting edge: identification of GL50, a novel B7-like protein that functionally binds to ICOS receptor. Journal of immunology (Baltimore, Md. : 1950) 179 10657606
2011 B7-h2 is a costimulatory ligand for CD28 in human. Immunity 126 21530327
2009 B7RP-1 blockade ameliorates autoimmunity through regulation of follicular helper T cells. Journal of immunology (Baltimore, Md. : 1950) 113 19155489
2000 Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS. International immunology 106 11007762
2002 Renal tubular epithelial expression of the costimulatory molecule B7RP-1 (inducible costimulator ligand). Journal of the American Society of Nephrology : JASN 71 12039981
2020 ICOSLG-mediated regulatory T-cell expansion and IL-10 production promote progression of glioblastoma. Neuro-oncology 65 31634400
2005 The immunomodulatory proteins B7-DC, B7-H2, and B7-H3 are differentially expressed across gestation in the human placenta. The American journal of pathology 65 16049332
2003 Impaired germinal center formation and recall T-cell-dependent immune responses in mice lacking the costimulatory ligand B7-H2. Blood 65 12714510
2014 Pattern recognition receptor signaling in human dendritic cells is enhanced by ICOS ligand and modulated by the Crohn's disease ICOSLG risk allele. Immunity 62 24837102
2004 Multiple combination therapies involving blockade of ICOS/B7RP-1 costimulation facilitate long-term islet allograft survival. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 60 15023144
2013 CagA-dependent downregulation of B7-H2 expression on gastric mucosa and inhibition of Th17 responses during Helicobacter pylori infection. Journal of immunology (Baltimore, Md. : 1950) 47 23997227
2006 CD28/CTLA-4--CD80/CD86 and ICOS--B7RP-1 costimulatory pathway in bronchial asthma. Allergy 37 16364152
2012 Single nucleotide polymorphisms in the promoter regions of Foxp3 and ICOSLG genes are associated with Alopecia areata. Clinical and experimental medicine 35 23196741
2021 Activated neutrophils polarize protumorigenic interleukin-17A-producing T helper subsets through TNF-α-B7-H2-dependent pathway in human gastric cancer. Clinical and translational medicine 33 34185422
2003 Expression of the costimulatory molecule B7-H2 (inducible costimulator ligand) by human airway epithelial cells. American journal of respiratory cell and molecular biology 30 12707012
2003 Disruption of the ICOS-B7RP-1 costimulatory pathway leads to enhanced hepatic immunopathology and increased gamma interferon production by CD4 T cells in murine schistosomiasis. Infection and immunity 30 12819093
2006 The ICOS-ligand B7-H2, expressed on human type II alveolar epithelial cells, plays a role in the pulmonary host defense system. European journal of immunology 29 16552709
2013 A functional variant at miR-24 binding site in B7-H2 alters susceptibility to gastric cancer in a Chinese Han population. Molecular immunology 28 23688438
2001 Differential expression of inducible costimulator-ligand splice variants: lymphoid regulation of mouse GL50-B and human GL50 molecules. Journal of immunology (Baltimore, Md. : 1950) 27 11390480
2009 Functional B7.2 and B7-H2 molecules on myeloma cells are associated with a growth advantage. Clinical cancer research : an official journal of the American Association for Cancer Research 26 19188146
2010 The regulation of T-cell cytokine production by ICOS-B7H2 interactions at the human fetomaternal interface. Immunology and cell biology 25 20733594
2003 Potent activity of soluble B7RP-1-Fc in therapy of murine tumors in syngeneic hosts. International journal of cancer 22 12478666
2006 The role of the ICOS/B7RP-1 T cell costimulatory pathway in murine experimental autoimmune uveoretinitis. European journal of immunology 21 17039566
2003 Involvement of ICOS-B7RP-1 costimulatory pathway in the regulation of immune responses to Leishmania major and Nippostrongylus brasiliensis infections. Immunology letters 19 14556978
2005 B7RP-1 is not required for the generation of Th2 responses in a model of allergic airway inflammation but is essential for the induction of inhalation tolerance. Journal of immunology (Baltimore, Md. : 1950) 16 15728513
2010 Impact of female cigarette smoking on circulating B cells in vivo: the suppressed ICOSLG, TCF3, and VCAM1 gene functional network may inhibit normal cell function. Immunogenetics 15 20217071
2007 ICOS/B7RP-1 interference in mouse kidney transplantation. Transplantation 15 17667814
2005 Antagonism between MyD88- and TRIF-dependent signals in B7RP-1 up-regulation. European journal of immunology 15 15884053
2005 The interaction between ICOS and B7RP-1 is not required for the development of experimental murine allergic conjunctivitis. Biochemical and biophysical research communications 13 16289109
2021 ICOSL in host defense at epithelial barriers: lessons from ICOSLG deficiency. Current opinion in immunology 11 33756276
2021 Mifepristone inhibited the expression of B7-H2, B7-H3, B7-H4 and PD-L2 in adenomyosis. Reproductive biology and endocrinology : RB&E 11 34289871
2009 Functional hierarchy and relative contribution of the CD28/B7 and ICOS/B7-H2 costimulatory pathways to T cell-mediated delayed-type hypersensitivity. Cellular immunology 11 19249753
2020 The combination of novel immune checkpoints HHLA2 and ICOSLG: A new system to predict survival and immune features in esophageal squamous cell carcinoma. Genes & diseases 10 35224157
2023 ICOS/ICOSLG and PD-1 Co-Expression is Associated with the Progression of Colorectal Precancerous- Carcinoma Immune Microenvironment. Journal of inflammation research 9 36915615
2023 ICOSLG-associated immunological landscape and diagnostic value in oral squamous cell carcinoma: a prospective cohort study. Frontiers in cell and developmental biology 9 37842091
2009 Defining dose-response relationships in the therapeutic blockade of B7RP-1-dependent immune responses. European journal of pharmacology 9 19292985
2009 Expression and function of the inducible costimulator ligand B7-H2 in human airway smooth muscle cells. Allergology international : official journal of the Japanese Society of Allergology 9 19776675
2004 Role of the B7RP-1/ICOS pathway in renal tubular epithelial antigen presentation to CD4+ Th1 and Th2 cells. Nephron. Experimental nephrology 9 15361696
2003 The role of inducible co-stimulator (ICOS)/B7-related protein-1 (B7RP-1) interaction in the functional development of Peyer's patches. Immunology letters 9 12853164
2022 The immune checkpoint ICOSLG is a relapse-predicting biomarker and therapeutic target in infant t(4;11) acute lymphoblastic leukemia. iScience 8 35800767
2010 Contribution of B7RP-1/ICOS co-stimulation to lethal acute GVHD. Pediatric transplantation 8 20136724
2015 Soluble B7-H2 as a novel marker in early evaluation of the severity of acute pancreatitis. Laboratory medicine 7 25918189
2024 ICOSLG Is Associated with Anti-PD-1 and Concomitant Antihistamine Treatment Response in Advanced Melanoma. International journal of molecular sciences 5 39596506
2012 Expression of ICOSLG on mouse hematologic neoplasm cell lines and their influence on cytotoxicity in allogeneic mixed lymphocyte reactions. Leukemia & lymphoma 4 21958057
2012 Effects of ICOSLG expressed in mouse hematological neoplasm cell lines in the GVL reaction. Bone marrow transplantation 4 22732700
2023 ICOSLG acts as an oncogene to promote glycolysis, proliferation, migration, and invasion in gastric cancer cells. Archives of biochemistry and biophysics 3 38081339
2009 Regulation of T cell response by blocking the ICOS signal with the B7RP-1-specific small antibody fragment isolated from human antibody phage library. mAbs 2 20065650
2003 Interaction of B7RP-1 with ICOS negatively regulates antigen presentation by B cells. Inflammation 2 14527172
2020 The B7 family molecules in oral squamous cell carcinoma: a systematic review. Part II: B7-1, B7-2, B7-H2, B7-H3, B7-H4, B7-H5 (VISTA), B7-H6 and B7-H7. Postepy dermatologii i alergologii 1 41001137
2026 RUNX1 recruitment of GCN5 in keratinocytes upregulates ICOSLG and promotes T cell activation in the psoriasis microenvironment. Experimental & molecular medicine 0 42243529
2015 [Correlation of Plasma Co-stimulatory Molecules B7-H2 and B7-H3 with Platelet Auto-antibodies in Patients with Immune Thrombocytopenic Purpura]. Zhongguo shi yan xue ye xue za zhi 0 26314449

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