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
File:PBB GE IL21 221271 at tn.png
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	[1]	[2]

Interleukin-21 also known as 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. 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)