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).
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ abcdParrish-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. PMID11081504. S2CID4428126.
^ abHabib 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. PMID12093291.
^ abIannello A, Boulassel MR, Samarani S, Tremblay C, Toma E, Routy JP, Ahmad A (May 2010). "IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication". Journal of Leukocyte Biology. 87 (5): 857–67. doi:10.1189/jlb.1009701. PMID20103765. S2CID21961522.
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. PMID16138102. S2CID12667905.
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. PMID12504082.
Zhang SQ, Chen B, Luo X, Xu CZ (July 2004). "[Cloning and expression of human interleukin-21 cDNA in E.coli]". Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi = Chinese Journal of Cellular and Molecular Immunology. 20 (4): 406–9. PMID15207081.
