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IL21
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2OQP, 3TGX
Identifiers
Aliases	IL21, CVID11, IL-21, Za11, interleukin 21
External IDs	OMIM: 605384; MGI: 1890474; HomoloGene: 11032; GeneCards: IL21; OMA:IL21 - orthologs
Gene location (Human) Chr. Chromosome 4 (human) Band 4q27 Start 122,610,108 bp End 122,621,066 bp
Gene location (Mouse) Chr. Chromosome 3 (mouse) Band 3|3 B Start 37,276,908 bp End 37,286,785 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle lymph node appendix buccal mucosa cell tonsil rectum urinary bladder left testis right testis gallbladder Top expressed in spermatocyte spermatid mesenteric lymph nodes thymus triceps brachii muscle submandibular gland anterior horn of spinal cord central gray substance of midbrain More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytokine activity interleukin-2 receptor binding cytokine receptor binding Cellular component intracellular anatomical structure extracellular space extracellular region Biological process positive regulation of inflammatory response positive regulation of cytokine production cell maturation positive regulation of B cell proliferation positive regulation of tissue remodeling positive regulation of T cell proliferation immune response positive regulation of cell population proliferation positive regulation of interleukin-17 production positive regulation of natural killer cell mediated cytotoxicity signal transduction tyrosine phosphorylation of STAT protein positive regulation of tyrosine phosphorylation of STAT protein regulation of signaling receptor activity interleukin-21-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 59067 60505 Ensembl ENSG00000138684 ENSMUSG00000027718 UniProt Q9HBE4 Q9ES17 RefSeq (mRNA) NM_021803 NM_001207006 NM_021782 NM_001291041 RefSeq (protein) NP_001193935 NP_068575 NP_001277970 NP_068554 Location (UCSC) Chr 4: 122.61 – 122.62 Mb Chr 3: 37.28 – 37.29 Mb PubMed search
Wikidata
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Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.

Interleukin-21 is a cytokine that has potent regulatory effects on cells of the immune system, including natural killer (NK) cells and cytotoxic T cells that can destroy virally infected or cancerous cells. This cytokine induces cell division/proliferation in its target cells.

Gene

The human IL-21 gene is about 8.43kb, mapped to chromosome 4 and 180kb from IL-2 gene, and the mRNA product is 616 nucleotides long.

Tissue and cell distribution

IL-21 is expressed in activated human CD4 T cells but not in most other tissues. In addition, IL-21 expression is up-regulated in T_h2 and T_h17 subsets of T helper cells, as well as T follicular cells. In fact, it was shown that IL-21 can be used to identify peripheral T follicular helper cells. Furthermore, IL-21 is expressed in NK T cells regulating the function of these cells.

Interleukin-21 is also produced by Hodgkin's lymphoma (HL) cancer cells (which is surprising because IL-21 was thought to be produced only in T cells). This observation may explain a great deal of the behavior of classical Hodgkin's lymphoma including clusters of other immune cells gathered around HL cells in cultures. Targeting IL-21 may be a potential treatment or possibly a test for HL.

Receptor

The IL-21 receptor (IL-21R) is expressed on the surface of T, B and NK cells. IL-21r is similar in structure to the receptors for other type I cytokines like IL-2R or IL-15 and requires dimerization with the common gamma chain (γc) in order to bind IL-21. When bound to IL-21, the IL-21 receptor acts through the Jak/STAT pathway, utilizing Jak1 and Jak3 and a STAT3 homodimer to activate its target genes.

Clinical relevance

Role in allergies

It has been shown that IL-21R knock-out mice express higher levels of IgE and lower levels of IgG1 than normal mice after antigen exposure. IgE levels decreased after mice were injected with IL-21. This has implications for the role of IL-21 in controlling allergic responses because of the role of IgE in hypersensitivity type 1 responses. IL-21 has been tried as therapy for alleviating allergic responses. It was shown to be successful in decreasing pro-inflammatory cytokines produced by T cells in addition to decreasing IgE levels in a mouse model for rhinitis (nasal passage inflammation). A study using mice with peanut allergies showed that systemic treatment of IL-21 was an effective means of mitigating the allergic response. This has strong implications for the pharmacological development of IL-21 for controlling both localized and systemic allergies.

Role in cancer immunotherapy

A role for IL-21 in modulating the differentiation programming of human T cells was first reported by Li et al., where it was shown to enrich for a population of central memory-type CTL with a unique CD28+ CD127hi CD45RO+ phenotype with IL-2 producing capacity. Tumor-reactive antigen-specific CTL generated by priming in the presence of IL-21 led to a stable, 'helper-independent' phenotype. IL-21 is also noted to have anti-tumour effects through continued and increased CD8+ cell response to achieve enduring tumor immunity.

IL-21 was approved for Phase 1 clinical trials in metastatic melanoma (MM) and renal cell carcinoma (RCC) patients. It was shown to be safe for administration with flu-like symptoms as side effects. Dose-limiting toxicities included low lymphocyte, neutrophil, and thrombocyte count as well as hepatotoxicity. According to the Response Evaluation Criteria in Solid Tumors (RECIST) response scale, 2 out of 47 MM patients and 4 out of 19 RCC patients showed complete and partial responses, respectively. In addition, there was an increase of perforin, granzyme B, IFN-γ, and CXCR3 mRNA in peripheral NK cells and CD8 T cells. This suggested that IL-21 enhances the CD8 effector functions thus leading to anti-tumor response. IL-21 proceeded to Phase 2 clinical trials where it was administered alone or coupled with drugs as sorafinib and rituximab.

Role in viral infections

IL-21 may be a critical factor in the control of persistent viral infections. IL-21 (or IL-21R) knock-out mice infected with chronic LCMV (lymphocytic choriomeningitis virus) were not able to overcome chronic infection compared to normal mice. Besides, these mice with impaired IL-21 signaling had more dramatic exhaustion of LCMV-specific CD8+ T cells, suggesting that IL-21 produced by CD4+ T cells is required for sustained CD8+ T cell effector activity and then, for maintaining immunity to resolve persistent viral infection. Thus, IL-21 may contribute to the mechanism by which CD4+ T helper cells orchestrate the immune system response to viral infections.

In HIV infected subjects, IL-21 has been reported to critically improve the HIV-specific cytotoxic T cell responses and NK cell functions. It has also been shown that HIV-specific CD4 T cells from “HIV controllers” (rare individuals who don’t progress to AIDS by controlling the virus replication without treatment) are able to produce significantly more IL-21 than those of progressors. In addition, IL-21 producing virus specific CD8 T cells were also preferentially found in HIV controllers. These data and the fact that IL-21 stimulated CD8 or NK cells are able to inhibit HIV viral replication in vitro, show that this cytokine could potentially be useful for anti-HIV therapeutics.

Drug development

An antibody to IL-21 is in development for multiple inflammatory conditions (Clinicaltrials.gov entries).

References

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9. Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS, Mackay CR (July 2004). "T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells". Journal of Immunology. 173 (1): 68–78. doi:10.4049/jimmunol.173.1.68. PMID 15210760.
10. Wei L, Laurence A, Elias KM, O'Shea JJ (November 2007). "IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner". The Journal of Biological Chemistry. 282 (48): 34605–10. doi:10.1074/jbc.M705100200. PMC 2323680. PMID 17884812.
11. Wurster AL, Rodgers VL, Satoskar AR, Whitters MJ, Young DA, Collins M, Grusby MJ (October 2002). "Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells". The Journal of Experimental Medicine. 196 (7): 969–77. doi:10.1084/jem.20020620. PMC 2194031. PMID 12370258.
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14. Lamprecht B, Kreher S, Anagnostopoulos I, Jöhrens K, Monteleone G, Jundt F, Stein H, Janz M, Dörken B, Mathas S (October 2008). "Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha". Blood. 112 (8): 3339–47. doi:10.1182/blood-2008-01-134783. PMID 18684866.
15. Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ (October 2000). "Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain". Proceedings of the National Academy of Sciences of the United States of America. 97 (21): 11439–44. Bibcode:2000PNAS...9711439O. doi:10.1073/pnas.200360997. PMC 17218. PMID 11016959.
16. Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K (July 2001). "Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex". Journal of Immunology. 167 (1): 1–5. doi:10.4049/jimmunol.167.1.1. PMID 11418623.
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Further reading

• Sivakumar PV, Foster DC, Clegg CH (June 2004). "Interleukin-21 is a T-helper cytokine that regulates humoral immunity and cell-mediated anti-tumour responses". Immunology. 112 (2): 177–82. doi:10.1111/j.1365-2567.2004.01886.x. PMC 1782493. PMID 15147560.
• Leonard WJ, Spolski R (September 2005). "Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation". Nature Reviews. Immunology. 5 (9): 688–98. doi:10.1038/nri1688. PMID 16138102. S2CID 12667905.
• Brandt K, Singh PB, Bulfone-Paus S, Rückert R (2007). "Interleukin-21: a new modulator of immunity, infection, and cancer". Cytokine & Growth Factor Reviews. 18 (3–4): 223–32. doi:10.1016/j.cytogfr.2007.04.003. PMID 17509926.
• Flores I, Casaseca T, Martinez-A C, Kanoh H, Merida I (April 1996). "Phosphatidic acid generation through interleukin 2 (IL-2)-induced alpha-diacylglycerol kinase activation is an essential step in IL-2-mediated lymphocyte proliferation". The Journal of Biological Chemistry. 271 (17): 10334–40. doi:10.1074/jbc.271.17.10334. PMID 8626603.
• Vosshenrich CA, Di Santo JP (March 2001). "Cytokines: IL-21 joins the gamma(c)-dependent network?". Current Biology. 11 (5): R175-7. doi:10.1016/S0960-9822(01)00087-2. PMID 11267886. S2CID 18207386.
• Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K (July 2001). "Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex". Journal of Immunology. 167 (1): 1–5. doi:10.4049/jimmunol.167.1.1. PMID 11418623.
• Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S (October 2002). "IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response". Journal of Immunology. 169 (7): 3600–5. doi:10.4049/jimmunol.169.7.3600. PMID 12244150.
• Zhang JL, Foster D, Sebald W (January 2003). "Human IL-21 and IL-4 bind to partially overlapping epitopes of common gamma-chain". Biochemical and Biophysical Research Communications. 300 (2): 291–6. doi:10.1016/S0006-291X(02)02836-X. PMID 12504082.
• Strengell M, Matikainen S, Sirén J, Lehtonen A, Foster D, Julkunen I, Sareneva T (June 2003). "IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells". Journal of Immunology. 170 (11): 5464–9. doi:10.4049/jimmunol.170.11.5464. PMID 12759422.
• Brandt K, Bulfone-Paus S, Foster DC, Rückert R (December 2003). "Interleukin-21 inhibits dendritic cell activation and maturation". Blood. 102 (12): 4090–8. doi:10.1182/blood-2003-03-0669. PMID 12893770.
• Sivori S, Cantoni C, Parolini S, Marcenaro E, Conte R, Moretta L, Moretta A (December 2003). "IL-21 induces both rapid maturation of human CD34+ cell precursors towards NK cells and acquisition of surface killer Ig-like receptors". European Journal of Immunology. 33 (12): 3439–47. doi:10.1002/eji.200324533. PMID 14635054.
• Pène J, Gauchat JF, Lécart S, Drouet E, Guglielmi P, Boulay V, Delwail A, Foster D, Lecron JC, Yssel H (May 2004). "Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells". Journal of Immunology. 172 (9): 5154–7. doi:10.4049/jimmunol.172.9.5154. PMID 15100251.
• Strengell M, Julkunen I, Matikainen S (August 2004). "IFN-alpha regulates IL-21 and IL-21R expression in human NK and T cells". Journal of Leukocyte Biology. 76 (2): 416–22. doi:10.1189/jlb.1003488. PMID 15178704. S2CID 17666508.
• Zhang SQ, Chen B, Luo X, Xu CZ (July 2004). "". Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi = Chinese Journal of Cellular and Molecular Immunology. 20 (4): 406–9. PMID 15207081.
• Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, Qi CF, Hwu P, Shaffer DJ, Akilesh S, Roopenian DC, Morse HC, Lipsky PE, Leonard WJ (November 2004). "Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6". Journal of Immunology. 173 (9): 5361–71. doi:10.4049/jimmunol.173.9.5361. PMID 15494482.
• Mehta DS, Wurster AL, Weinmann AS, Grusby MJ (February 2005). "NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression". Proceedings of the National Academy of Sciences of the United States of America. 102 (6): 2016–21. Bibcode:2005PNAS..102.2016M. doi:10.1073/pnas.0409512102. PMC 548571. PMID 15684054.

• Genes on human chromosome 4
• Interleukins