Interleukin 21

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.[5][6][7]

IL21
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIL21, CVID11, IL-21, Za11, interleukin 21
External IDsOMIM: 605384 MGI: 1890474 HomoloGene: 11032 GeneCards: IL21
Gene location (Human)
Chr.Chromosome 4 (human)[1]
Band4q27Start122,610,108 bp[1]
End122,621,066 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
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 MbChr 3: 37.22 – 37.23 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][8] 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.[5][7]

Tissue and cell distribution

IL-21 is expressed in activated human CD4+ T cells but not in most other tissues.[5] In addition, IL-21 expression is up-regulated in Th2 and Th17 subsets of T helper cells, as well as T follicular cells.[9][10][11] In fact, it was shown that IL-21 can be used to identify peripheral T follicular helper cells.[12] Furthermore, IL-21 is expressed in NK T cells regulating the function of these cells.[13]

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.[14]

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[15] or IL-15 and requires dimerization with the common gamma chain (γc) in order to bind IL-21.[16][17] 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.[17]

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.[18] 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).[19] A study using mice with peanut allergies showed that systemic treatment of IL-21 was an effective means of mitigating the allergic response.[20] 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.[21] IL-21 is also noted to have anti-tumour effects through continued and increased CD8+ cell response to achieve enduring tumor immunity.[22]

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.[23]

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.[24] 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[25][26] and NK cell functions.[27] 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.[26] In addition, IL-21 producing virus specific CD8 T cells were also preferentially found in HIV controllers.[28] These data and the fact that IL-21 stimulated CD8 or NK cells are able to inhibit HIV viral replication in vitro,[26][27] 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. GRCh38: Ensembl release 89: ENSG00000138684 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000027718 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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 (November 2000). "Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function". Nature. 408 (6808): 57–63. Bibcode:2000Natur.408...57P. doi:10.1038/35040504. PMID 11081504. S2CID 4428126.
  6. Kuchen S, Robbins R, Sims GP, Sheng C, Phillips TM, Lipsky PE, Ettinger R (November 2007). "Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell-B cell collaboration". Journal of Immunology. 179 (9): 5886–96. doi:10.4049/jimmunol.179.9.5886. PMID 17947662.
  7. "Entrez Gene: IL21 interleukin 21".
  8. Parrish-Novak J, Foster DC, Holly RD, Clegg CH (November 2002). "Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses". Journal of Leukocyte Biology. 72 (5): 856–63. PMID 12429707. Archived from the original on 2009-01-08. Retrieved 2008-02-20.
  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.
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  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. doi:10.1073/pnas.200360997. PMC 17218. PMID 11016959.
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  17. Habib T, Senadheera S, Weinberg K, Kaushansky K (July 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): 8725–31. doi:10.1021/bi0202023. PMID 12093291.
  18. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, Morse HC, Liu C, Schwartzberg PL, Leonard WJ (November 2002). "A critical role for IL-21 in regulating immunoglobulin production". Science. 298 (5598): 1630–4. Bibcode:2002Sci...298.1630O. doi:10.1126/science.1077002. PMID 12446913. S2CID 6210513.
  19. Hiromura Y, Kishida T, Nakano H, Hama T, Imanishi J, Hisa Y, Mazda O (November 2007). "IL-21 administration into the nostril alleviates murine allergic rhinitis". Journal of Immunology. 179 (10): 7157–65. doi:10.4049/jimmunol.179.10.7157. PMID 17982108.
  20. 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 (December 2007). "IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice". Journal of Immunology. 179 (12): 8554–61. doi:10.4049/jimmunol.179.12.8554. PMID 18056403.
  21. Li Y, Bleakley M, Yee C (August 2005). "IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response". Journal of Immunology. 175 (4): 2261–9. doi:10.4049/jimmunol.175.4.2261. PMID 16081794.
  22. Moroz A, Eppolito C, Li Q, Tao J, Clegg CH, Shrikant PA (July 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". Journal of Immunology. 173 (2): 900–9. doi:10.4049/jimmunol.173.2.900. PMID 15240677.
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  24. Johnson LD, Jameson SC (June 2009). "Immunology. A chronic need for IL-21". Science. 324 (5934): 1525–6. doi:10.1126/science.1176487. PMID 19541985. S2CID 5345355.
  25. White L, Krishnan S, Strbo N, Liu H, Kolber MA, Lichtenheld MG, Pahwa RN, Pahwa S (May 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.
  26. 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 (January 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". Journal of Virology. 85 (2): 733–41. doi:10.1128/JVI.02030-10. PMC 3020027. PMID 21047960.
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Further reading
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