Interleukin 21

Interleukin 21
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2OQP​, 3TGX​
Identifiers
Symbols	IL21 ; CVID11; IL-21; Za11
External IDs	OMIM: 605384 MGI: 1890474 HomoloGene: 11032 GeneCards: IL21 Gene
Gene ontology Molecular function • cytokine activity • cytokine receptor binding • interleukin-2 receptor binding Cellular component • extracellular space • intracellular Biological process • positive regulation of cytokine production • positive regulation of natural killer cell cytokine production • immune response • signal transduction • positive regulation of cell proliferation • positive regulation of B cell proliferation • positive regulation of interleukin-10 production • positive regulation of interleukin-17 production • positive regulation of natural killer cell differentiation • positive regulation of tissue remodeling • positive regulation of T cell proliferation • tyrosine phosphorylation of Stat3 protein • positive regulation of tyrosine phosphorylation of Stat1 protein • positive regulation of tyrosine phosphorylation of Stat3 protein • positive regulation of interferon-gamma biosynthetic process • positive regulation of natural killer cell mediated cytotoxicity • cell maturation • positive regulation of inflammatory response Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	59067	60505
Ensembl	ENSG00000138684	ENSMUSG00000027718
UniProt	Q9HBE4	Q9ES17
RefSeq (mRNA)	NM_001207006	NM_001291041
RefSeq (protein)	NP_001193935	NP_001277970
Location (UCSC)	Chr 4: 122.61 – 122.62 Mb	Chr 3: 37.22 – 37.23 Mb
PubMed search

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.^[1][2][3]

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.^[1][4] 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.^[1][3]

Tissue and cell distribution

IL-21 is expressed in activated human CD4⁺ T cells but not in most other tissues.^[1] 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.^[5][6][7] Furthermore, IL-21 is expressed in NK T cells regulating the function of these cells.^[8]

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.^[9]

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^[10] or IL-15 and requires dimerization with the common gamma chain (γc) in order to bind IL-21.^[11][12] 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.^[12]

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.^[13] 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).^[14] A study using mice with peanut allergies showed that systemic treatment of IL-21 was an effective means of mitigating the allergic response.^[15] 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.^[16] IL-21 is also noted to have anti-tumour effects through continued and increased CD8+ cell response to achieve enduring tumor immunity.^[17]

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.^[18]

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.^[19] 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^[20][21] and NK cell functions.^[22] 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.^[21] In addition, IL-21 producing virus specific CD8 T cells were also preferentially found in HIV controllers.^[23] These data and the fact that IL-21 stimulated CD8 or NK cells are able to inhibit HIV viral replication in vitro,^[21][22] 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

1. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, Johnston J, Madden K, Xu W, West J, Schrader S, Burkhead S, Heipel M, Brandt C, Kuijper JL, Kramer J, Conklin D, Presnell SR, Berry J, Shiota F, Bort S, Hambly K, Mudri S, Clegg C, Moore M, Grant FJ, Lofton-Day C, Gilbert T, Rayond F, Ching A, Yao L, Smith D, Webster P, Whitmore T, Maurer M, Kaushansky K, Holly RD, Foster D (2000). "Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function". Nature 408 (6808): 57–63. doi:10.1038/35040504. PMID 11081504.
2. Kuchen S, Robbins R, Sims GP, Sheng C, Phillips TM, Lipsky PE, Ettinger R (2007). "Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell-B cell collaboration". J. Immunol. 179 (9): 5886–96. doi:10.4049/jimmunol.179.9.5886. PMID 17947662.
3. "Entrez Gene: IL21 interleukin 21".
4. Parrish-Novak J, Foster DC, Holly RD, Clegg CH (2002). "Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses". J. Leukoc. Biol. 72 (5): 856–63. PMID 12429707.
5. Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS, Mackay CR (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". J. Immunol. 173 (1): 68–78. doi:10.4049/jimmunol.173.1.68. PMID 15210760.
6. Wei L, Laurence A, Elias KM, O'Shea JJ (2007). "IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner". J. Biol. Chem. 282 (48): 34605–10. doi:10.1074/jbc.M705100200. PMC 2323680. PMID 17884812.
7. Wurster AL, Rodgers VL, Satoskar AR, Whitters MJ, Young DA, Collins M, Grusby MJ (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". J. Exp. Med. 196 (7): 969–77. doi:10.1084/jem.20020620. PMC 2194031. PMID 12370258.
8. Coquet JM, Kyparissoudis K, Pellicci DG, Besra G, Berzins SP, Smyth MJ, Godfrey DI (2007). "IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production". J. Immunol. 178 (5): 2827–34. doi:10.4049/jimmunol.178.5.2827. PMID 17312126.
9. Lamprecht B, Kreher S, Anagnostopoulos I, Jöhrens K, Monteleone G, Jundt F, Stein H, Janz M, Dörken B, Mathas S (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): 3339–3347. doi:10.1182/blood-2008-01-134783. PMID 18684866.
10. Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ (2000). "Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain". Proc. Natl. Acad. Sci. U.S.A. 97 (21): 11439–11444. doi:10.1073/pnas.200360997. PMC 17218. PMID 11016959.
11. Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K (2001). "Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex". J. Immunol. 167 (1): 1–5. doi:10.4049/jimmunol.167.1.1. PMID 11418623.
12. Habib T, Senadheera S, Weinberg K, Kaushansky K (2002). "The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3". Biochemistry 41 (27): 8725–8731. doi:10.1021/bi0202023. PMID 12093291.
13. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, Morse HC, Liu C, Schwartzberg PL, Leonard WJ (2002). "A critical role for IL-21 in regulating immunoglobulin production". Science 298 (5598): 1630–4. doi:10.1126/science.1077002. PMID 12446913.
14. Hiromura Y, Kishida T, Nakano H, Hama T, Imanishi J, Hisa Y, Mazda O (2007). "IL-21 administration into the nostril alleviates murine allergic rhinitis". J. Immunol. 179 (10): 7157–65. doi:10.4049/jimmunol.179.10.7157. PMID 17982108.
15. Kishida T, Hiromura Y, Shin-Ya M, Asada H, Kuriyama H, Sugai M, Shimizu A, Yokota Y, Hama T, Imanishi J, Hisa Y, Mazda O (2007). "IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice". J. Immunol. 179 (12): 8554–61. doi:10.4049/jimmunol.179.12.8554. PMID 18056403.
16. Li Y, Bleakley M, Yee C (2005). "IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response". J. Immunol. 175 (4): 2261–9. doi:10.4049/jimmunol.175.4.2261. PMID 16081794.
17. Moroz A, Eppolito C, Li Q, Tao J, Clegg CH, Shrikant PA (2004). "IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21". J. Immunol. 173 (2): 900–909. doi:10.4049/jimmunol.173.2.900. PMID 15240677.
18. Søndergaard H, Skak K (2009). "IL-21: roles in immunopathology and cancer therapy". Tissue Antigens 74 (6): 467–79. doi:10.1111/j.1399-0039.2009.01382.x. PMID 19845910.
19. Johnson LD, Jameson SC (2009). "Immunology. A chronic need for IL-21". Science 324 (5934): 1525–1526. doi:10.1126/science.1176487. PMID 19541985.
20. White L, Krishnan S, Strbo N, Liu H, Kolber MA, Lichtenheld MG, Pahwa RN, Pahwa S (2007). "Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV)". Blood 109 (9): 3873–80. doi:10.1182/blood-2006-09-045278. PMC 1874576. PMID 17192392.
21. Chevalier MF, Jülg B, Pyo A, Flanders M, Ranasinghe S, Soghoian DZ, Kwon DS, Rychert J, Lian J, Muller MI, Cutler S, McAndrew E, Jessen H, Pereyra F, Rosenberg ES, Altfeld M, Walker BD, Streeck H (2011). "HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function". J. Virol. 85 (2): 733–41. doi:10.1128/JVI.02030-10. PMC 3020027. PMID 21047960.
22. Iannello A, Boulassel MR, Samarani S, Tremblay C, Toma E, Routy JP, Ahmad A (2010). "IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication". J. Leukoc. Biol. 87 (5): 857–67. doi:10.1189/jlb.1009701. PMID 20103765.
23. Williams LD, Bansal A, Sabbaj S, Heath SL, Song W, Tang J, Zajac AJ, Goepfert PA (2011). "Interleukin-21-producing HIV-1-specific CD8 T cells are preferentially seen in elite controllers". J. Virol. 85 (5): 2316–2324. doi:10.1128/JVI.01476-10. PMC 3067790. PMID 21159862.

Further reading

• Sivakumar PV, Foster DC, Clegg CH (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 (2005). "Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation". Nat. Rev. Immunol. 5 (9): 688–98. doi:10.1038/nri1688. PMID 16138102.
• Brandt K, Singh PB, Bulfone-Paus S, Rückert R (2007). "Interleukin-21: a new modulator of immunity, infection, and cancer". Cytokine Growth Factor Rev. 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 (1996). "Phosphatidic acid generation through interleukin 2 (IL-2)-induced alpha-diacylglycerol kinase activation is an essential step in IL-2-mediated lymphocyte proliferation". J. Biol. Chem. 271 (17): 10334–40. doi:10.1074/jbc.271.17.10334. PMID 8626603.
• Vosshenrich CA, Di Santo JP (2001). "Cytokines: IL-21 joins the gamma(c)-dependent network?". Curr. Biol. 11 (5): R175–7. doi:10.1016/S0960-9822(01)00087-2. PMID 11267886.
• Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K (2001). "Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex". J. Immunol. 167 (1): 1–5. doi:10.4049/jimmunol.167.1.1. PMID 11418623.
• Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S (2002). "IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response". J. Immunol. 169 (7): 3600–5. doi:10.4049/jimmunol.169.7.3600. PMID 12244150.
• Zhang JL, Foster D, Sebald W (2003). "Human IL-21 and IL-4 bind to partially overlapping epitopes of common gamma-chain". Biochem. Biophys. Res. Commun. 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 (2003). "IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells". J. Immunol. 170 (11): 5464–9. doi:10.4049/jimmunol.170.11.5464. PMID 12759422.
• Brandt K, Bulfone-Paus S, Foster DC, Rückert R (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 (2003). "IL-21 induces both rapid maturation of human CD34+ cell precursors towards NK cells and acquisition of surface killer Ig-like receptors". Eur. J. Immunol. 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 (2004). "Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells". J. Immunol. 172 (9): 5154–7. doi:10.4049/jimmunol.172.9.5154. PMID 15100251.
• Strengell M, Julkunen I, Matikainen S (2004). "IFN-alpha regulates IL-21 and IL-21R expression in human NK and T cells". J. Leukoc. Biol. 76 (2): 416–22. doi:10.1189/jlb.1003488. PMID 15178704.
• Zhang SQ, Chen B, Luo X, Xu CZ (2004). "[Cloning and expression of human interleukin-21 cDNA in E.coli]". Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 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 (2004). "Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6". J. Immunol. 173 (9): 5361–71. doi:10.4049/jimmunol.173.9.5361. PMID 15494482.
• Mehta DS, Wurster AL, Weinmann AS, Grusby MJ (2005). "NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression". Proc. Natl. Acad. Sci. U.S.A. 102 (6): 2016–21. doi:10.1073/pnas.0409512102. PMC 548571. PMID 15684054.