Interleukin 21

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Interleukin 21
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols IL21 ; CVID11; IL-21; Za11
External IDs OMIM605384 MGI1890474 HomoloGene11032 GeneCards: IL21 Gene
RNA expression pattern
PBB GE IL21 221271 at tn.png
More reference expression data
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:
123.53 – 123.54 Mb
Chr 3:
37.22 – 37.23 Mb
PubMed search [1] [2]

Interleukin-21 also known as 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.


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[edit]

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 Th2 and Th17 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]


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[edit]

Role in allergies[edit]

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[edit]

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[edit]

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[edit]

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


  1. ^ a b c d Parrish-Novak J, Dillon S, Nelson A, Hammond A, Sprecher C, Gross J et al. (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 G, Sheng C, Phillips T, Lipsky P et al. (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. ^ a b "Entrez Gene: IL21 interleukin 21". 
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  13. ^ Ozaki K, Spolski R, Feng C, Qi C, Cheng J, Sher A et al. (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 et al. (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 et al. (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 C, Shrikant P (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. 
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  20. ^ White L, Krishnan S, Strbo N, Liu H, Kolber M, Lichtenheld M et al. (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. 
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Further reading[edit]