Affinage

IL21

Interleukin-21 · UniProt Q9HBE4

Length
162 aa
Mass
18.7 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 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

IL-21 is a pleiotropic CD4+ T cell-derived cytokine that orchestrates B cell humoral immunity, T cell effector and memory programs, and immune regulation, signaling through the IL-21R to activate JAK/STAT pathways (PMID:23440042, PMID:26170288). Loss-of-function mutation in its receptor causes a primary immunodeficiency, with aberrant IL-21R trafficking abrogating ligand binding and defective STAT1/STAT3/STAT5 phosphorylation that impairs B cell proliferation, class-switching, T cell cytokine production, and NK cytotoxicity (PMID:23440042). In B cells, IL-21 acts cell-intrinsically to maintain germinal center reactions: it sustains Bcl-6 expression by blocking BCR-driven proteasomal degradation (cooperatively with IL-4), accelerates cell cycle entry through AKT/S6 signaling, and tunes dark-zone selection via cyclin D3 and Foxo1, while human plasma cell differentiation requires B cell-intrinsic STAT3 (PMID:20142430, PMID:20048285, PMID:28875978, PMID:35801309, PMID:37466652). The strength of this B cell signal is set extracellularly by heparan sulfate N-sulfation, which is downregulated in GC B cells to desensitize them and upregulated in antibody-secreting cell precursors (PMID:36800411). In T cells, IL-21 is both an effector and a self-amplifying autocrine signal—IL-6/STAT3 induces IL-21, which feeds back via STAT3 recruitment to its promoter and STAT3/NFAT-dependent long-range enhancer looping to drive Th17 differentiation and suppress Foxp3 (PMID:17581589, PMID:18209077, PMID:27067007). IL-21 also restrains regulatory T cells, directly limiting Treg expansion and triggering Treg death via Bcl-2 family suppression and an Akt-mTOR-NLRP3-caspase-1 pyroptosis axis, and promotes CD8+ T cell stemness through metabolic quiescence dependent on oxidative phosphorylation (PMID:23696736, PMID:30654048, PMID:37164271, PMID:32123114). IL-21 transcription is gated by activating inputs (c-Rel and SUMO-state-dependent c-Maf controlling Daxx/HDAC2 versus CBP/p300 occupancy) and repressive inputs (NR2F6 binding that is released during Tfh differentiation) (PMID:20639489, PMID:30059018, PMID:31509749). These activities make IL-21 a driver of autoimmune and inflammatory disease in models of EAE, type 1 diabetes, Th2/helminth pathology, and immune-checkpoint-induced thyroiditis (PMID:17581589, PMID:18779574, PMID:16778988, PMID:37196065).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 Medium

    Established that IL-21 transcription is inducible by interferon signaling while IL-21R is reciprocally downregulated, defining an early layer of cross-cytokine control of the IL-21 axis.

    Evidence EMSA/promoter analysis and STAT3 phosphorylation in human NK and T cells

    PMID:15178704

    Open questions at the time
    • GAS element occupancy shown by EMSA not chromatin-context ChIP
    • Functional consequence of receptor downregulation on B cell output not addressed
  2. 2006 High

    Showed IL-21 reshapes innate and Th2 effector function—suppressing NKG2D-dependent NK cytotoxicity via DAP10 while augmenting macrophage IL-4R/IL-13R responsiveness—broadening its role beyond adaptive immunity.

    Evidence DAP10 luciferase reporter and cytotoxicity/degranulation assays in human NK/CD8 cells; IL-21R-KO mice in helminth infection

    PMID:16424177 PMID:16778988

    Open questions at the time
    • Direct transcription factors driving DAP10 repression not identified
    • Mechanism of IL-4R/IL-13R upregulation downstream of IL-21R unresolved
  3. 2007 High

    Identified IL-21 as an autocrine cytokine necessary and sufficient for Th17 differentiation, placing it downstream of IL-6/STAT3 and explaining its role in autoimmune EAE.

    Evidence IL-21-deficient mice, STAT3/RORγt pathway analysis, EAE model

    PMID:17581589

    Open questions at the time
    • Did not resolve chromatin/promoter basis of IL-21 induction
    • Relative contribution of autocrine vs paracrine IL-21 in vivo not quantified
  4. 2008 High

    Defined the molecular basis of IL-21 self-amplification by showing STAT3 is recruited to the IL-21 promoter to drive an autocrine transcriptional loop in human T cells.

    Evidence Promoter ChIP, STAT3 inhibition and siRNA with cytokine readout in human T cells

    PMID:18209077

    Open questions at the time
    • Distal regulatory elements not yet examined
    • Stoichiometry/kinetics of the feedback loop not defined
  5. 2008 High

    Demonstrated IL-21R signaling is required for type 1 diabetes pathogenesis, linking the cytokine to organ-specific autoimmunity via Th17 expansion and Reg gene suppression.

    Evidence IL-21R-KO NOD mice with glucose monitoring, histology, and Reg gene quantification

    PMID:18779574

    Open questions at the time
    • Cellular target of IL-21 driving islet infiltration not isolated
    • Mechanism connecting IL-21 to Reg gene levels unresolved
  6. 2009 Medium

    Revealed context-dependent IL-21 effects on transformed lymphocytes—apoptosis in follicular lymphoma versus pro-growth JAK3/STAT3 signaling in ALK+ ALCL and Burkitt lines.

    Evidence Caspase/mitochondrial assays in lymphoma lines; recombinant IL-21 and IL-21R siRNA with JAK3/STAT3 readout

    PMID:17624663 PMID:19608866

    Open questions at the time
    • Determinants of pro-apoptotic vs pro-growth outcome not defined
    • Cell-line findings not validated in primary tumors in these studies
  7. 2010 High

    Established IL-21 as a B cell-intrinsic regulator of the germinal center via Bcl-6 maintenance and showed human plasma cell differentiation strictly requires B cell-intrinsic STAT3.

    Evidence IL-21R-deficient bone marrow chimeras with immunization; human STAT1/STAT3 loss-of-function patient B cells

    PMID:20048285 PMID:20142430

    Open questions at the time
    • How IL-21/STAT3 sustains Bcl-6 mechanistically not resolved here
    • STAT5 contribution to B cell program not addressed
  8. 2010 High

    Identified c-Rel as a direct transcriptional activator of IL-21 in T cells and dissociated IL-21's role in Tfh formation from GC B cell development by rescue.

    Evidence c-Rel KO mice, promoter ChIP, IL-21 protein rescue, flow cytometry

    PMID:20639489

    Open questions at the time
    • Interplay of c-Rel with STAT3 at the locus not defined
    • Why IL-21 rescues Tfh but not GC B cells in rel-/- not explained
  9. 2013 High

    Showed IL-21 cell-intrinsically restrains Treg expansion and that this restraint is required for effective antiviral CD8 responses, framing IL-21 as a suppressor of immune regulation.

    Evidence IL-21R-KO mice in chronic LCMV with Treg depletion and IL-2 complex experiments

    PMID:23696736

    Open questions at the time
    • Molecular mechanism limiting Treg proliferation not defined here
    • Direct vs indirect effect on CD8 responses not fully separated
  10. 2013 Medium

    Connected IL-21 to autoimmunity through SUMO-dependent c-Maf/NR4A2 regulatory inputs and to malignant B cell proliferation in CLL, expanding both transcriptional control and disease relevance.

    Evidence NR4A2 siRNA with IL-21 rescue and EAE; CD40L+IL-21 co-culture of CLL cells with gene signature and patient LN detection

    PMID:23437182 PMID:24014238

    Open questions at the time
    • NR4A2 mechanism on IL-21 locus indirect
    • CLL signature causal drivers not dissected
  11. 2015 High

    Resolved that STAT1 and STAT3 exert opposing, non-redundant control of IL-21-driven gene programs in CD4+ T cells, including Tbx21/Ifng and in vivo antiviral outcomes.

    Evidence Stat1- and Stat3-deficient mice with RNA-Seq, chronic LCMV, and human patients with distinct STAT defects

    PMID:26170288

    Open questions at the time
    • How STAT1/STAT3 balance is set per cell type unresolved
    • Direct target genes of each STAT not all mapped
  12. 2015 Medium

    Identified Btk as an amplifier of IL-21 signaling controlling nuclear STAT1 phosphorylation in B cells, and linked IL-21 to intestinal IgA via TGFβ1-dependent class switching.

    Evidence Btk inhibitor with subcellular STAT1 fractionation in B cell line; Il21-deficient mice and Th17 reconstitution for IgA CSR

    PMID:25586558 PMID:25724205

    Open questions at the time
    • Btk's selectivity for nuclear vs cytoplasmic STAT1 mechanistically unclear
    • Direct vs autocrine-TGFβ1 contributions to IgA not fully separated
  13. 2016 High

    Defined IL-21's metabolic and epigenetic logic—driving OXPHOS-dependent CD8 stemness, NK ADCC enhancement, and a STAT3/NFAT-dependent long-range enhancer loop controlling its own expression.

    Evidence Ldha deletion and metabolic profiling with adoptive transfer; NK ADCC/ERK/STAT1 assays with xenografts; 3C/4C chromatin conformation with STAT3/NFAT ChIP

    PMID:27067007 PMID:27435400 PMID:32123114

    Open questions at the time
    • How the distal enhancer is silenced in Tregs only partly defined
    • Transcription-factor circuitry coupling metabolism to stemness not fully mapped
  14. 2018 High

    Showed IL-21 transcription is epigenetically gated by c-Maf SUMOylation state, which switches the locus between Daxx/HDAC2 repression and CBP/p300-mediated histone acetylation, driving diabetogenic extrafollicular help.

    Evidence Transgenic NOD mice with SUMO-mutant c-Maf, ChIP at Il21 promoter, CBP/p300 inhibitor

    PMID:30059018

    Open questions at the time
    • Upstream signals controlling c-Maf SUMOylation not defined
    • Interaction with STAT3/c-Rel inputs at the locus unresolved
  15. 2019 High

    Established active repression and apoptosis arms of the axis: NR2F6 directly silences Il21 in resting T cells until Tfh differentiation, while IL-21 kills Foxp3+ Tregs via Bcl-2 family suppression to amplify Th2 inflammation.

    Evidence NR2F6 ChIP and Nr2f6-KO mice with IL-21R-blockade rescue; mixed chimeras and competitive transfer with Bcl-2 family apoptosis analysis

    PMID:30654048 PMID:31509749

    Open questions at the time
    • Signal that releases NR2F6 from the locus during Tfh differentiation not identified
    • Bcl-2 family target(s) most responsible for Treg death not pinpointed
  16. 2020 Medium

    Demonstrated IL-21 can reprogram differentiated effector CD8 T cells toward central-memory states when chromatin at the CD28 locus is opened, with pSTAT3 binding driving CD28/CD62L re-expression.

    Evidence HDACi plus IL-21 with ChIP/ATAC at CD28, pSTAT3 binding, and memory transcriptional signatures

    PMID:32213626

    Open questions at the time
    • Stability of reprogrammed state in vivo not established here
    • Genome-wide pSTAT3 targets in reprogramming not mapped
  17. 2023 High

    Refined IL-21's germinal-center mechanism through cell-cycle and signal-strength control—cyclin D3/Foxo1-tuned dark-zone entry and heparan-sulfate-gated IL-21 bioavailability—and extended its pathogenic role to checkpoint-induced thyroiditis and Treg pyroptosis in chronic rhinosinusitis.

    Evidence IL-21R-KO GC analyses with cyclin D3/Foxo1; Ndst1-KO B cells with HS biochemistry; scRNA-seq plus IL-21-KO ICI-thyroiditis model; pyroptosis markers and Akt-mTOR-NLRP3 inhibition in ECRS

    PMID:36800411 PMID:37164271 PMID:37196065 PMID:37466652

    Open questions at the time
    • How Foxo1 is regulated by IL-21 signaling not fully defined
    • Connection between HS desensitization and downstream STAT output not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple transcriptional inputs (c-Rel, c-Maf, NR2F6, STAT3/NFAT enhancer looping) and the STAT1/STAT3 balance are integrated to set IL-21 dose and downstream program in each cell type remains unresolved.
  • No unified model linking locus regulation to per-cell output
  • Quantitative rules for IL-21 signal strength across receiving cell types not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3
Partners
IL21RSTAT1STAT3

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 IL-21 is produced by Th17 cells and acts as an autocrine cytokine sufficient and necessary for Th17 differentiation. IL-6 induces IL-21 in activated T cells via STAT3 (but not ROR-γ). IL-21 in turn potently induces Th17 differentiation and suppresses Foxp3 expression, requiring both STAT3 and ROR-γ (Rorc). IL-21 deficiency impairs Th17 generation and protects against experimental autoimmune encephalomyelitis. Genetic knockout (IL-21-deficient mice), cytokine stimulation assays, STAT3/ROR-γ pathway analysis, EAE model Nature High 17581589
2010 IL-21 signaling acts directly on B cells (B cell-intrinsic) to maintain Bcl-6 expression in germinal center B cells, regulate GC persistence and proliferation, promote plasma cell and memory B cell formation, and support affinity maturation. CD3-expressing cells are the source of IL-21 acting on B cells in vivo. Bone marrow chimeras with IL-21R-deficient and wild-type cells, protein antigen immunization, flow cytometry, gene expression analysis The Journal of experimental medicine High 20142430
2010 IL-21-induced B cell differentiation into plasma cells in humans requires B cell-intrinsic STAT3 signaling. STAT3 loss-of-function mutations abolish IL-21-driven naive B cell differentiation into plasma cells and reduce antigen-specific memory B cells. STAT1 deficiency has no effect on IL-21-induced immunoglobulin secretion in vitro. Studies of patients with inactivating STAT1 or STAT3 mutations, in vitro IL-21 stimulation assays, immunoglobulin secretion measurement The Journal of experimental medicine High 20048285
2008 IL-21 induces its own expression in human T cells via an autocrine loop: IL-21 activates STAT3, which is recruited to the IL-21 gene promoter to enhance IL-21 transcription. Pharmacological inhibition or siRNA knockdown of STAT3 prevents IL-21 auto-induction. STAT3 inhibition, siRNA knockdown, promoter ChIP assay, cytokine stimulation of human peripheral blood and lamina propria T cells Journal of immunology High 18209077
2013 Loss-of-function mutations in IL21R cause primary immunodeficiency. The IL-21R Arg201Leu mutation causes aberrant trafficking of IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of STAT1, STAT3, and STAT5, resulting in impaired B cell proliferation, immunoglobulin class-switching, T cell cytokine production, and NK cell cytotoxicity. Exome sequencing, candidate gene sequencing, receptor trafficking assays, IL-21 ligand binding assays, STAT phosphorylation assays, functional lymphocyte assays The Journal of experimental medicine High 23440042
2006 IL-21 down-regulates NKG2D surface expression on human NK and CD8+ T cells by dramatically reducing DAP10 promoter activity, thereby attenuating NKG2D-mediated NK cell cytotoxicity and degranulation. Conversely, IL-21 induces expression of NK activation receptors NKp30 and 2B4, and costimulatory receptor CD28 on CD8+ T cells. Cell culture with human primary NK and CD8+ T cells, NKG2D redirected lysis assays, degranulation assays, DAP10 luciferase reporter construct, transcript analysis Journal of immunology High 16424177
2006 The IL-21 receptor augments Th2 effector function and alternative macrophage activation in vivo. IL-21 significantly augments IL-4Rα and IL-13Rα1 expression in macrophages, resulting in increased FIZZ1 mRNA and arginase-1 activity following IL-4 and IL-13 stimulation. IL-21R deficiency reduces granulomatous inflammation, liver fibrosis, and Th2 cytokine responses to helminth infection. IL-21R-knockout mice infected with Schistosoma mansoni and Nippostrongylus brasiliensis, soluble IL-21R-Fc blockade, in vitro macrophage stimulation assays The Journal of clinical investigation High 16778988
2008 IL-21 signaling through IL-21R is critical for the development of type 1 diabetes in the NOD mouse. IL-21R-knockout NOD mice are devoid of pancreatic lymphocytic infiltration and are protected from diabetes. This correlates with reduced Th17 cells and significantly higher expression of Reg family genes whose products protect against diabetes. IL-21R KO backcrossed to NOD mice, glucose monitoring, histological analysis, T cell and Treg functional assays, Reg gene mRNA quantification PNAS High 18779574
2010 The NF-κB transcription factor c-Rel is required for IL-21 gene expression in T lymphocytes. c-Rel binds a specific site in the proximal il21 promoter, confirmed in vitro and in vivo by ChIP. IL-21 mRNA and protein are reduced in CD4+ T cells from rel−/− mice. Administration of IL-21 protein rescues Tfh cell development but not germinal center B cell development in rel−/− mice. c-Rel KO mice, ChIP assay for c-Rel promoter binding, IL-21 rescue experiments, flow cytometry of T and B cell populations Journal of immunology High 20639489
2015 STAT1 and STAT3 have opposing roles in IL-21 signaling in CD4+ T cells. IL-21 activates both STAT1 and STAT3; STAT1 phosphorylation is augmented in Stat3-deficient CD4+ T cells. RNA-Seq in Stat1- and Stat3-deficient mice shows both are critical for IL-21-mediated gene regulation. STAT1 and STAT3 differentially regulate Tbx21 and Ifng expression, with opposing in vivo roles during chronic LCMV infection. Stat1- and Stat3-deficient mice, RNA-Seq, phosphorylation assays, chronic LCMV infection model, patient samples (STAT3-deficient/STAT1 gain-of-function patients) PNAS High 26170288
2013 IL-21 directly inhibits Treg cell expansion in a cell-intrinsic manner during chronic LCMV infection. In IL-21R−/− mice, virus-driven Treg cell expansion is greatly enhanced. IL-21 restricts Treg proliferation, and augmented Treg expansion (via IL-2/anti-IL-2 immune complexes) impairs antiviral T cell responses and promotes viral persistence. IL-21R KO mice, LCMV infection model, Treg depletion, IL-2/anti-IL-2 complex administration, flow cytometry of CD8+ T cell function PLoS pathogens High 23696736
2016 IL-21 promotes CD8+ T cell stemness and stem cell memory T cell (TSCM) formation through maintaining metabolic quiescence dependent on oxidative phosphorylation, in contrast to IL-2 which drives aerobic glycolysis via LDH induction. LDH inhibition combined with IL-21 synergistically increases TSCM formation and antitumor responses. Metabolic profiling (OXPHOS vs glycolysis), LDH inhibition, Ldha gene deletion, adoptive transfer tumor models, transcriptomic analysis PNAS High 32123114
2019 IL-21 directly promotes apoptosis of Foxp3+ regulatory T cells by interfering with Bcl-2 family gene expression, thereby indirectly sustaining generation of inflammatory TH cells and TH2-driven asthmatic responses. This cell-intrinsic effect was demonstrated using mixed bone marrow chimeras and competitive adoptive transfer experiments. IL-21R-deficient mice, mixed bone marrow chimeras, adoptive transfer of Treg cells, Treg depletion experiments, in vitro apoptosis assays with Bcl-2 family gene analysis The Journal of allergy and clinical immunology High 30654048
2013 CD40L combined with IL-21 is sufficient to induce robust proliferation of CLL cells, defining an IL-21-induced gene signature containing JAK/STAT and apoptosis pathway components. IL-21 production by CD4+CXCR5+ follicular helper T cells was detected in lymph nodes, where IL-21 RNA and protein were also found. Co-culture of CLL cells with autologous T cells or recombinant CD40L+IL-21, gene expression profiling, in situ detection of IL-21 in lymph node samples, ELISA Blood Medium 24014238
2004 IFN-α/β enhances IL-21 mRNA expression in activated human T cells and an IFN-γ activation site (GAS) element in the IL-21 promoter binds STAT1, STAT2, STAT3, and STAT4 in IFN-α/β-stimulated NK or T cell extracts. Conversely, IFN-α/β down-regulates IL-21R expression in NK and T cells, resulting in reduced STAT3 phosphorylation and DNA binding after IL-21 stimulation. Promoter analysis with gel shift (EMSA), mRNA expression analysis, STAT3 phosphorylation assays in human NK and T cells Journal of leukocyte biology Medium 15178704
2016 IL-21 enhances NK cell signal transduction via activation of ERK and STAT1 when responding to cetuximab-coated pancreatic tumor cells, and increases NK cell-mediated ADCC, IFN-γ secretion, and T cell chemotaxis. In vivo, mIL-21 combined with cetuximab significantly inhibits tumor growth in pancreatic cancer xenograft models. NK cell activation assays (ADCC, IFN-γ ELISA), ERK/STAT1 phosphorylation analysis, subcutaneous and intraperitoneal xenograft models Clinical cancer research Medium 27435400
2015 Bruton's tyrosine kinase (Btk) amplifies IL-21 signaling in human B cells by mediating nuclear (but not cytoplasmic) STAT1 phosphorylation downstream of IL-21 combined with BCR and CD40 signals. Btk inhibition suppresses IL-21-induced B cell differentiation and IgG production. Btk inhibitor treatment, phosphorylation assays distinguishing nuclear vs cytoplasmic STAT1, BJAB cell line signaling assays, flow cytometry, ELISA Rheumatology Medium 25724205
2017 IL-4 and IL-21 cooperate to maintain high Bcl-6 protein levels required for germinal center formation. IL-21 prevents BCR-mediated proteasomal degradation of Bcl-6. Combined B cell-intrinsic loss of IL-4 and IL-21 signaling almost completely eliminates the GC response in vivo. Bcl-6 protein stability assays in stimulated B cells, conditional KO mice for IL-4R and IL-21R signaling, flow cytometry of GC populations Immunology and cell biology Medium 28875978
2013 NR4A2 (nuclear receptor) controls full Th17 differentiation via autocrine IL-21 signaling. When NR4A2 expression is blocked by siRNA, Th17 cells express RORγt but fail to produce IL-17 and IL-21, and this differentiation defect is rescued by exogenous IL-21. In vivo NR4A2 siRNA treatment reduces Th17 effector responses and protects against EAE. siRNA knockdown of NR4A2 in vitro, exogenous IL-21 rescue experiment, in vivo siRNA treatment, EAE model, flow cytometry PLoS one Medium 23437182
2009 IL-21 induces apoptosis of follicular lymphoma cells (carrying t(14;18)) via caspase-8 and caspase-3 activation, reduction of mitochondrial membrane potential, decreased Bcl-2 expression, and increased Bax expression. In contrast, IL-21 stimulates growth of Burkitt lymphoma and T cell leukemia lines. In vitro IL-21 treatment of lymphoma cell lines, caspase activity assays, mitochondrial membrane potential measurement, Bcl-2/Bax protein expression Cancer letters Medium 17624663
2009 IL-21 contributes to JAK3/STAT3 activation and cell growth in ALK+ anaplastic large cell lymphoma. Recombinant IL-21 enhances JAK3/STAT3 activation and increases cell growth; siRNA knockdown of IL-21R decreases STAT3 activation and cell growth. IL-21R expression is independent of NPM-ALK. Recombinant IL-21 treatment, IL-21R siRNA knockdown, JAK3/STAT3 phosphorylation assays, cell growth assays, NPM-ALK overexpression/knockdown The American journal of pathology Medium 19608866
2016 IL-21 enhances IL-21 gene expression through a long-range chromatin interaction mechanism. A conserved noncoding sequence 49 kb upstream of IL-21 acts as an enhancer in a STAT3- and NFAT-dependent manner. IL-6/STAT3 signaling induces dynamic chromatin looping between the IL-21 promoter and distal enhancer. This interaction is absent in regulatory T cells where IL-21 expression is repressed. Chromosome conformation capture (3C/4C), ChIP for STAT3 and NFAT, CTCF binding assays, enhancer reporter assays, naive vs regulatory T cell comparisons Journal of immunology High 27067007
2018 SUMO-defective c-Maf preferentially transactivates Il21 by selectively inhibiting recruitment of the Daxx/HDAC2 repressor complex to the Il21 promoter and enhancing histone acetylation via CBP and p300. This epigenetic mechanism promotes extrafollicular helper T cell development and IL-21-mediated diabetogenesis in NOD mice. Transgenic NOD mice with WT or SUMOylation-mutant c-Maf, ChIP for Daxx/HDAC2 and histone acetylation at Il21 promoter, CBP/p300 inhibitor (CBP30) treatment, diabetes incidence monitoring The Journal of clinical investigation High 30059018
2019 The orphan nuclear receptor NR2F6 directly binds the IL-21 promoter and a conserved noncoding sequence near the Il21 gene in resting CD4+ T cells to repress IL-21 transcription. During Tfh cell differentiation, this NR2F6 DNA interaction is abolished, allowing Il21 expression. Enhanced Tfh cell accumulation in Nr2f6-deficient mice is reversed by blocking IL-21R signaling. ChIP demonstrating NR2F6 binding to IL-21 promoter and CNS, Nr2f6-deficient mice, IL-21R blockade rescue experiment, flow cytometry Cell reports High 31509749
2023 Heparan sulfate (HS) regulates IL-21 bioavailability and signal strength in germinal center B cells. N-deacetylase and N-sulfotransferase 1 (Ndst1)-mediated N-sulfation of HS in B cells promotes IL-21 binding and signaling. GC B cells have reduced HS sulfation compared to non-GC cells, attenuating IL-21 signaling. Ndst1 is down-regulated in GC B cells and up-regulated in ASC precursors, enabling selective desensitization to IL-21 in the GC and strong signaling in ASC differentiation. IL-21 binding assays on GC vs non-GC B cells, Ndst1-deficient B cell analysis, HS sulfation biochemical assays, in vivo GC and ASC differentiation analysis Science immunology High 36800411
2022 IL-21 acts as a key regulator of the initial B cell response by accelerating cell cycle progression and rate of cycle entry, increasing B cell contribution to the germinal center. This effect occurs across a range of BCR affinities and correlates with elevated AKT and S6 phosphorylation. The increased proliferation mechanistically explains IL-21-mediated promotion of plasma cell differentiation. B cell transfer and immunization models with IL-21R-deficient and WT cells, cell cycle analysis, AKT and S6 phosphorylation assays, flow cytometry EMBO reports High 35801309
2023 IL-21 shapes germinal center polarization by promoting selection of light zone GC B cells for dark zone entry and triggering cyclin D3 upregulation in GC B cells to tune inertial cell cycling. IL-21R deficiency results in smaller GC skewed toward light zone phenotype. Foxo1 regulation links IL-21 signaling to dark zone GC B cell formation. IL-21R-deficient mice, cyclin D3 expression analysis, GC B cell light/dark zone flow cytometric analysis, immunization-induced and spontaneous autoimmune GC models The Journal of experimental medicine High 37466652
2023 IL-21 secreted by intrathyroidal TFH and TPH cells drives clonally expanded cytotoxic CXCR6+CD8+ T cells in ICI-thyroiditis. IL-21 treatment of human CD8+ T cells upregulates IFN-γ, granzyme B, and CXCR6. Genetic deletion of IL-21 signaling in mice protects from thyroid immune infiltration after ICI treatment. Single-cell RNA sequencing of thyroid specimens, in vitro CD8+ T cell stimulation with IL-21, IL-21 genetic KO mouse model of IRAEs, immunohistochemistry Science translational medicine High 37196065
2023 IL-21 induces pyroptosis of Treg cells via activation of the Akt-mTOR-NLRP3-caspase 1 signaling axis in eosinophilic chronic rhinosinusitis. Akt-mTOR inhibition prevents IL-21-induced pyroptosis in human and mouse Treg cells. Blocking IL-21/IL-21R signaling reduces eosinophil numbers and increases Treg cell percentage in ECRS mice. Western blot analysis of pyroptosis markers, electron microscopy of pyroptotic cells, Akt-mTOR inhibitor treatment, IL-21/IL-21R neutralization in mouse model, flow cytometry The Journal of allergy and clinical immunology High 37164271
2015 IL-21 promotes intestinal IgA class switch recombination and IgA production through TGFβ1-dependent mechanisms. IL-21 combined with retinoic acid induces IgA+ B cell development and drives autocrine TGFβ1 production to initiate IgA CSR. IL-21 also promotes intestinal B cell homing through α4β7 expression. Il17- and Il21-deficient mice, T cell reconstitution of TCRβxδ−/− mice with antigen-specific Th17 cells, IL-21 neutralization, B cell IgA CSR assays Mucosal immunology Medium 25586558
2020 Histone deacetylase inhibitors (HDACi) combined with IL-21 reprogram differentiated human effector CD8+ T cells to central memory-like T cells. HDACi increases H3 acetylation and chromatin accessibility at the CD28 promoter, enabling IL-21-mediated pSTAT3 binding to the CD28 locus and subsequent upregulation of CD28 and CD62L. Reprogrammed cells show stable memory transcriptional signature (Lef1, Tcf7). ChIP for H3 acetylation and STAT3 binding at CD28 promoter (ATAC-seq for chromatin accessibility), flow cytometry for CD28/CD62L surface markers, functional proliferation assays Cancer immunology research Medium 32213626

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 1206 17581589
2010 IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. The Journal of experimental medicine 641 20142430
2012 Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PloS one 535 22279576
2018 IL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT-bet+ B cells in SLE. Nature communications 465 29717110
2010 B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. The Journal of experimental medicine 338 20048285
2007 IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. Journal of immunology (Baltimore, Md. : 1950) 314 17312126
2006 The IL-21 receptor augments Th2 effector function and alternative macrophage activation. The Journal of clinical investigation 284 16778988
2019 PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. JCI insight 249 31536480
2004 IL-21 induces the functional maturation of murine NK cells. Journal of immunology (Baltimore, Md. : 1950) 234 14764669
2020 Glypican-3-Specific CAR T Cells Coexpressing IL15 and IL21 Have Superior Expansion and Antitumor Activity against Hepatocellular Carcinoma. Cancer immunology research 222 31953246
2020 Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity. Proceedings of the National Academy of Sciences of the United States of America 191 32123114
2008 The role of IL-21 in regulating B-cell function in health and disease. Immunological reviews 188 18613830
2002 Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. Journal of leukocyte biology 188 12429707
2014 Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage. Frontiers in immunology 173 24600453
2008 IL-21 signaling is critical for the development of type I diabetes in the NOD mouse. Proceedings of the National Academy of Sciences of the United States of America 171 18779574
2013 Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. The Journal of experimental medicine 163 23440042
2004 Biology of IL-21 and the IL-21 receptor. Immunological reviews 159 15546387
2019 Clinical significance and immunobiology of IL-21 in autoimmunity. Journal of autoimmunity 156 30773373
2012 A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis research & therapy 146 23176102
2016 IL-21 Signaling in Immunity. F1000Research 145 26966515
2009 IL-21 and T follicular helper cells. International immunology 145 19933709
2016 IL-21 and T Cell Differentiation: Consider the Context. Trends in immunology 133 27389961
2009 IL-21: an executor of B cell fate. Journal of immunology (Baltimore, Md. : 1950) 126 19201828
2013 IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells. Blood 123 24014238
2011 IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. The American journal of pathology 117 21281812
2015 Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells. Proceedings of the National Academy of Sciences of the United States of America 110 26170288
2008 Autocrine regulation of IL-21 production in human T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 99 18209077
2006 IL-21 down-regulates NKG2D/DAP10 expression on human NK and CD8+ T cells. Journal of immunology (Baltimore, Md. : 1950) 96 16424177
2010 IL-21 regulates Th17 cells in rheumatoid arthritis. Human immunology 95 20079789
2015 Interleukin (IL)-21 promotes intestinal IgA response to microbiota. Mucosal immunology 93 25586558
2009 Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. Arthritis and rheumatism 86 19404967
2009 Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease. Inflammatory bowel diseases 81 19322899
2019 IL-21 Induces an Imbalance of Th17/Treg Cells in Moderate-to-Severe Plaque Psoriasis Patients. Frontiers in immunology 80 31440249
2015 IL-21: a pleiotropic cytokine with potential applications in oncology. Journal of immunology research 79 25961061
2021 New developments implicating IL-21 in autoimmune disease. Journal of autoimmunity 70 34224936
2010 Confirmation of an association between rs6822844 at the Il2-Il21 region and multiple autoimmune diseases: evidence of a general susceptibility locus. Arthritis and rheumatism 68 20112382
2013 Nuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signalling. PloS one 67 23437182
2013 IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection. PLoS pathogens 65 23696736
2015 Biological effects of IL-21 on different immune cells and its role in autoimmune diseases. Immunobiology 64 26466984
2010 Regulation of the IL-21 gene by the NF-κB transcription factor c-Rel. Journal of immunology (Baltimore, Md. : 1950) 62 20639489
2015 Advances in IL-21 biology - enhancing our understanding of human disease. Current opinion in immunology 60 25801685
2014 Human IL-21 and IL-21R deficiencies: two novel entities of primary immunodeficiency. Current opinion in pediatrics 60 25321844
2016 IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells. Clinical cancer research : an official journal of the American Association for Cancer Research 59 27435400
2017 Th9 cells promote antitumor immunity via IL-9 and IL-21 and demonstrate atypical cytokine expression in breast cancer. International immunopharmacology 56 28918288
2004 IFN-alpha regulates IL-21 and IL-21R expression in human NK and T cells. Journal of leukocyte biology 54 15178704
2009 IL-21: roles in immunopathology and cancer therapy. Tissue antigens 52 19845910
2018 IL-21 Selectively Protects CD62L+ NKT Cells and Enhances Their Effector Functions for Adoptive Immunotherapy. Journal of immunology (Baltimore, Md. : 1950) 51 30111631
2015 IL-21 and IL-4 Collaborate To Shape T-Dependent Antibody Responses. Journal of immunology (Baltimore, Md. : 1950) 50 26491200
2007 High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma. Cancer letters 48 17624663
2023 Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation. Science immunology 47 36800411
2010 Association of the AFF3 gene and IL2/IL21 gene region with juvenile idiopathic arthritis. Genes and immunity 47 20072139
2019 T Follicular Helper Cell Subsets and the Associated Cytokine IL-21 in the Pathogenesis and Therapy of Asthma. Frontiers in immunology 46 31921177
2017 IL4 and IL21 cooperate to induce the high Bcl6 protein level required for germinal center formation. Immunology and cell biology 46 28875978
2009 IL-21 contributes to JAK3/STAT3 activation and promotes cell growth in ALK-positive anaplastic large cell lymphoma. The American journal of pathology 45 19608866
2008 IL-21 augments natural killer effector functions in chronically HIV-infected individuals. AIDS (London, England) 44 18670213
2022 IL-21 has a critical role in establishing germinal centers by amplifying early B cell proliferation. EMBO reports 43 35801309
2021 The Roles of IL-17, IL-21, and IL-23 in the Helicobacter pylori Infection and Gastrointestinal Inflammation: A Review. Toxins 42 33924897
2011 Fine-mapping and transethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21. Arthritis and rheumatism 42 21425124
2023 IL-21 induces pyroptosis of Treg cells via Akt-mTOR-NLRP3-caspase 1 axis in eosinophilic chronic rhinosinusitis. The Journal of allergy and clinical immunology 41 37164271
2016 IL-21 signaling is essential for optimal host resistance against Mycobacterium tuberculosis infection. Scientific reports 39 27819295
2012 Gene-gene and gene-sex epistatic interactions of MiR146a, IRF5, IKZF1, ETS1 and IL21 in systemic lupus erythematosus. PloS one 39 23236436
2019 IL-21 promotes allergic airway inflammation by driving apoptosis of FoxP3+ regulatory T cells. The Journal of allergy and clinical immunology 38 30654048
2023 Clonally expanded, thyrotoxic effector CD8+ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis. Science translational medicine 37 37196065
2003 IL-21 and IL-21 receptor: a new cytokine pathway modulates innate and adaptive immunity. Immunologic research 37 14610289
2020 IFN-γ+ IL-17+ Th17 cells regulate fibrosis through secreting IL-21 in systemic scleroderma. Journal of cellular and molecular medicine 36 33157566
2015 Amplification of IL-21 signalling pathway through Bruton's tyrosine kinase in human B cell activation. Rheumatology (Oxford, England) 36 25724205
2008 Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families. Genes and immunity 34 18418394
2024 Cooperative Armoring of CAR and TCR T Cells by T Cell-Restricted IL15 and IL21 Universally Enhances Solid Tumor Efficacy. Clinical cancer research : an official journal of the American Association for Cancer Research 33 37910044
2012 The Interplay of IL-21 and BAFF in the Formation and Maintenance of Human B Cell Memory. Frontiers in immunology 33 22566888
2015 A pathogenetic role for IL-21 in primary Sjögren syndrome. Nature reviews. Rheumatology 32 25584898
2022 CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following stroke. Journal of neuroinflammation 31 35624463
2015 Increased IL-21 expression in chronic rhinosinusitis with nasalpolyps. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 31 25495679
2015 IL-21 and IL-21 receptor in the immunopathogenesis of multiple sclerosis. Journal of immunotoxicology 31 26507681
2019 Identification of a γc Receptor Antagonist That Prevents Reprogramming of Human Tissue-resident Cytotoxic T Cells by IL15 and IL21. Gastroenterology 30 31622625
2021 Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency. Journal of clinical immunology 29 33929673
2013 Comparison of vascular leak syndrome in mice treated with IL21 or IL2. Comparative medicine 29 23561933
2007 Role of IL-21 in immune-regulation and tumor immunotherapy. Cancer immunology, immunotherapy : CII 29 17447063
2020 Histone Deacetylase Inhibitors and IL21 Cooperate to Reprogram Human Effector CD8+ T Cells to Memory T Cells. Cancer immunology research 28 32213626
2019 Orphan Nuclear Receptor NR2F6 Suppresses T Follicular Helper Cell Accumulation through Regulation of IL-21. Cell reports 28 31509749
2019 Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases. Frontiers in cellular and infection microbiology 28 31867283
2016 The Biological Effects of IL-21 Signaling on B-Cell-Mediated Responses in Organ Transplantation. Frontiers in immunology 28 27602031
2011 IL-21 is an antitolerogenic cytokine of the late-phase alloimmune response. Diabetes 28 22013017
2022 Anti-GD2 Antibodies Conjugated to IL15 and IL21 Mediate Potent Antitumor Cytotoxicity against Neuroblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 27 35802683
2021 CD40L-Stimulated B Lymphocytes Are Polarized toward APC Functions after Exposure to IL-4 and IL-21. Journal of immunology (Baltimore, Md. : 1950) 27 34135061
2018 Defective IgA response to atypical intestinal commensals in IL-21 receptor deficiency reshapes immune cell homeostasis and mucosal immunity. Mucosal immunology 27 30087442
2007 IL-21 receptor expression determines the temporal phases of experimental autoimmune encephalomyelitis. Experimental neurology 27 18353312
2013 IL21 and IL21R polymorphisms and their interactive effects on serum IL-21 and IgE levels in patients with chronic hepatitis B virus infection. Human immunology 26 23354321
2008 Effective collaboration between IL-4 and IL-21 on B cell activation. Immunobiology 26 18656702
2012 Role of IL-21 and IL-21 receptor on B cells in HIV infection. Critical reviews in immunology 25 23216614
2018 SUMO-defective c-Maf preferentially transactivates Il21 to exacerbate autoimmune diabetes. The Journal of clinical investigation 24 30059018
2018 Pan-HDAC Inhibitors Restore PRDM1 Response to IL21 in CREBBP-Mutated Follicular Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research 24 30348636
2015 Association of IL-21 cytokine with severity of primary Sjögren syndrome dry eye. Cornea 24 25603233
2014 IL-21 as a therapeutic target in inflammatory disorders. Expert opinion on therapeutic targets 24 25162763
2016 Dynamic Long-Range Chromatin Interaction Controls Expression of IL-21 in CD4+ T Cells. Journal of immunology (Baltimore, Md. : 1950) 23 27067007
2016 CCL21/IL21-armed oncolytic adenovirus enhances antitumor activity against TERT-positive tumor cells. Virus research 23 27157859
2023 IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation. The Journal of experimental medicine 22 37466652
2018 Evaluating IL-21 as a Potential Therapeutic Target in Crohn's Disease. Gastroenterology research and practice 22 29849593
2012 Psoriasis, from pathogenesis to therapeutic strategies: IL-21 as a novel potential therapeutic target. Current pharmaceutical biotechnology 22 22250707
2022 LncRNA IL21-AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus. Clinical and translational medicine 21 36447054
2020 IL-21 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology 21 32060889

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