Details for: IL21

Gene ID: 59067

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: IL21

Ensembl ID: ENSG00000138684

Description: interleukin 21

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • T follicular helper cell CL0002038
    CSI 11.3
    rCSI 8.46%
    PRS 100

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [IL21](/details-gene/59067) (Interleukin-21) is a protein-coding gene located on chromosome 4q27 that encodes a potent immunomodulatory cytokine. As a member of the common gamma-chain (γc) family of cytokines, [IL21](/details-gene/59067) plays a critical role in regulating both innate and adaptive immune responses. Its primary functions include promoting the proliferation and differentiation of B cells, T cells, and natural killer (NK) cells. The expression profile of [IL21](/details-gene/59067) is highly specific, with its significance overwhelmingly concentrated in [T follicular helper cells](/details-cell/CL0002038), underscoring its central role in humoral immunity and the generation of antibody responses within germinal centers. Deficiencies in [IL21](/details-gene/59067) have been linked to immunodeficiency and inflammatory bowel disease ([Link](https://doi.org/10.1016/j.jaci.2014.02.034)). ## Cellular Roles and Expression Landscape The expression pattern of [IL21](/details-gene/59067) is remarkably restricted, establishing it as a key functional marker for a specific subset of helper T cells. - **Overall**, the gene's expression is most significant and defining in **[T follicular helper cells](/details-cell/CL0002038)** (CSI: 11.30). This highly localized expression is consistent with the primary role of Tfh cells in providing help to B cells during the germinal center reaction, a process heavily dependent on [IL21](/details-gene/59067) signaling. This focused expression suggests that the biological impact of [IL21](/details-gene/59067) is primarily channeled through the specialized functions of [T follicular helper cells](/details-cell/CL0002038), which orchestrate the maturation and differentiation of B cells into memory cells and long-lived plasma cells. ## Pathways and Molecular Function The molecular functions of [IL21](/details-gene/59067) are centered on its activity as an extracellular signaling molecule that modulates lymphocyte function. - **Molecular Function**: [IL21](/details-gene/59067) primarily exhibits [cytokine activity](/details-go/GO0005125) and binds to its specific receptor complex, which includes the common gamma chain, initiating downstream signaling cascades ([Link](https://doi.org/10.1074/jbc.m111.311084)). - **Biological Process**: The gene is integral to numerous immune processes. It is a critical factor for [T follicular helper cell differentiation](/details-go/GO0061470) and is essential for [germinal center b cell differentiation](/details-go/GO0002314). Beyond the germinal center, [IL21](/details-gene/59067) promotes the [positive regulation of b cell proliferation](/details-go/GO0030890), [positive regulation of t cell proliferation](/details-go/GO0042102), and enhances the cytotoxic activity of NK cells ([positive regulation of natural killer cell mediated cytotoxicity](/details-go/GO0045954)) ([Link](https://doi.org/10.1038/35040504)). It also contributes to antiviral immunity through its role in the [defense response to virus](/details-go/GO0051607). - **Signaling Pathways**: [IL21](/details-gene/59067) functions within the broader network of [Cytokine signaling in immune system](/details-reactome/R-HSA-1280215) and is a key component of the [Interleukin-2 family signaling](/details-reactome/R-HSA-451927) pathway. Its specific effects are mediated through the dedicated [Interleukin-21 signaling](/details-reactome/R-HSA-9020958) pathway, which primarily involves the activation of the JAK/STAT signaling cascade, leading to the [tyrosine phosphorylation of stat protein](/details-go/GO0007260). ## Research Directions Given its specific expression and potent immunomodulatory functions, [IL21](/details-gene/59067) presents significant opportunities for both basic research and clinical translation. ### Proposed Hypotheses 1. The highly restricted expression of [IL21](/details-gene/59067) to [T follicular helper cells](/details-cell/CL0002038) suggests that epigenetic mechanisms, such as DNA methylation or histone modifications at the [IL21](/details-gene/59067) locus, are uniquely programmed during Tfh differentiation and are dysregulated in autoimmune diseases characterized by excessive antibody production. 2. Given its role in promoting cell-mediated anti-tumor responses ([Link](https://doi.org/10.1111/j.1365-2567.2004.01886.x)), administering a long-acting form of [IL21](/details-gene/59067) in combination with CAR-T cell therapy could enhance the persistence and effector function of CAR-T cells in the solid tumor microenvironment, overcoming T-cell exhaustion. ### Key Experiment To test the second hypothesis, a synergistic anti-tumor effect could be evaluated in a preclinical solid tumor model (e.g., immunodeficient mice xenografted with a human tumor line and the corresponding CAR-T cells). One cohort would receive CAR-T cells alone, while the experimental cohort would receive CAR-T cells plus systemic administration of a clinically relevant, engineered [IL21](/details-gene/59067) variant with an extended half-life. Endpoints would include tumor growth inhibition, overall survival, and *ex vivo* analysis of tumor-infiltrating CAR-T cells to measure markers of proliferation (Ki-67), effector function (Granzyme B, IFN-γ), and exhaustion (PD-1, TIM-3, LAG-3). ### Therapeutic Potential [IL21](/details-gene/59067) itself holds considerable potential as a therapeutic agent for **activation** of the immune system. Its ability to bolster B cell, T cell, and NK cell responses makes it an attractive candidate for cancer immunotherapy and as a vaccine adjuvant. Recombinant [IL21](/details-gene/59067) could be used to stimulate anti-tumor immunity or enhance protective antibody responses. Conversely, blockade of the [IL21](/details-gene/59067) pathway could be a viable strategy for **inhibition** in antibody-mediated autoimmune diseases where Tfh cells and germinal center activity are pathogenic. However, because deficiency causes severe immunopathology ([Link](https://doi.org/10.1016/j.jaci.2014.02.034)), systemic inhibition would require careful consideration of potential side effects.

Genular Protein ID: 3434994508

Symbol: IL21_HUMAN

Name: Za11

UniProtKB Accession Codes:

Q9HBE4 A5J0L4

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CTD 1 ChEMBL 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 10 EMDB 1 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 23 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 2 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 1 RefSeq 2 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 11081504

Title: Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.

PubMed ID: 11081504

DOI: 10.1038/35040504

PubMed ID: 17673207

Title: Cloning and characterization of an isoform of interleukin-21.

PubMed ID: 17673207

DOI: 10.1016/j.febslet.2007.07.034

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15178704

Title: IFN-alpha regulates IL-21 and IL-21R expression in human NK and T cells.

PubMed ID: 15178704

DOI: 10.1189/jlb.1003488

PubMed ID: 15147560

Title: Interleukin-21 is a T-helper cytokine that regulates humoral immunity and cell-mediated anti-tumour responses.

PubMed ID: 15147560

DOI: 10.1111/j.1365-2567.2004.01886.x

PubMed ID: 17565991

Title: The existence of multiple conformers of interleukin-21 directs engineering of a superpotent analogue.

PubMed ID: 17565991

DOI: 10.1074/jbc.m701313200

PubMed ID: 22235133

Title: Crystal structure of interleukin-21 receptor (IL-21R) bound to IL-21 reveals that sugar chain interacting with WSXWS motif is integral part of IL-21R.

PubMed ID: 22235133

DOI: 10.1074/jbc.m111.311084

PubMed ID: 24746753

Title: Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency.

PubMed ID: 24746753

DOI: 10.1016/j.jaci.2014.02.034

Sequence Information:

  • Length: 162
  • Mass: 18653
  • Checksum: 54EFD4EED3AB97FE
  • Sequence:
    • MRSSPGNMER IVICLMVIFL GTLVHKSSSQ GQDRHMIRMR QLIDIVDQLK NYVNDLVPEF 
LPAPEDVETN CEWSAFSCFQ KAQLKSANTG NNERIINVSI KKLKRKPPST NAGRRQKHRL 
TCPSCDSYEK KPPKEFLERF KSLLQKMIHQ HLSSRTHGSE DS