Interleukin 21
Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.[5][6][7]
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
[edit]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
[edit]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
[edit]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
[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.[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
[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.[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
[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.[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
[edit]An antibody to IL-21 is in development for multiple inflammatory conditions (Clinicaltrials.gov entries).
References
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- ^ Wurster AL, Rodgers VL, Satoskar AR, Whitters MJ, Young DA, Collins M, Grusby MJ (October 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". The Journal of Experimental Medicine. 196 (7): 969–77. doi:10.1084/jem.20020620. PMC 2194031. PMID 12370258.
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Further reading
[edit]- Sivakumar PV, Foster DC, Clegg CH (June 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 (September 2005). "Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation". Nature Reviews. Immunology. 5 (9): 688–98. doi:10.1038/nri1688. PMID 16138102. S2CID 12667905.
- Brandt K, Singh PB, Bulfone-Paus S, Rückert R (2007). "Interleukin-21: a new modulator of immunity, infection, and cancer". Cytokine & Growth Factor Reviews. 18 (3–4): 223–32. doi:10.1016/j.cytogfr.2007.04.003. PMID 17509926.[verification needed]
- Flores I, Casaseca T, Martinez-A C, Kanoh H, Merida I (April 1996). "Phosphatidic acid generation through interleukin 2 (IL-2)-induced alpha-diacylglycerol kinase activation is an essential step in IL-2-mediated lymphocyte proliferation". The Journal of Biological Chemistry. 271 (17): 10334–40. doi:10.1074/jbc.271.17.10334. PMID 8626603.
- Vosshenrich CA, Di Santo JP (March 2001). "Cytokines: IL-21 joins the gamma(c)-dependent network?". Current Biology. 11 (5): R175-7. doi:10.1016/S0960-9822(01)00087-2. PMID 11267886. S2CID 18207386.
- Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K (July 2001). "Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex". Journal of Immunology. 167 (1): 1–5. doi:10.4049/jimmunol.167.1.1. PMID 11418623.
- Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S (October 2002). "IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response". Journal of Immunology. 169 (7): 3600–5. doi:10.4049/jimmunol.169.7.3600. PMID 12244150.
- 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. PMID 12504082.
- Strengell M, Matikainen S, Sirén J, Lehtonen A, Foster D, Julkunen I, Sareneva T (June 2003). "IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells". Journal of Immunology. 170 (11): 5464–9. doi:10.4049/jimmunol.170.11.5464. PMID 12759422.
- Brandt K, Bulfone-Paus S, Foster DC, Rückert R (December 2003). "Interleukin-21 inhibits dendritic cell activation and maturation". Blood. 102 (12): 4090–8. doi:10.1182/blood-2003-03-0669. PMID 12893770.[verification needed]
- Sivori S, Cantoni C, Parolini S, Marcenaro E, Conte R, Moretta L, Moretta A (December 2003). "IL-21 induces both rapid maturation of human CD34+ cell precursors towards NK cells and acquisition of surface killer Ig-like receptors". European Journal of Immunology. 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 (May 2004). "Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells". Journal of Immunology. 172 (9): 5154–7. doi:10.4049/jimmunol.172.9.5154. PMID 15100251.
- Strengell M, Julkunen I, Matikainen S (August 2004). "IFN-alpha regulates IL-21 and IL-21R expression in human NK and T cells". Journal of Leukocyte Biology. 76 (2): 416–22. doi:10.1189/jlb.1003488. PMID 15178704. S2CID 17666508.
- 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. 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 (November 2004). "Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6". Journal of Immunology. 173 (9): 5361–71. doi:10.4049/jimmunol.173.9.5361. PMID 15494482.
- Mehta DS, Wurster AL, Weinmann AS, Grusby MJ (February 2005). "NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression". Proceedings of the National Academy of Sciences of the United States of America. 102 (6): 2016–21. Bibcode:2005PNAS..102.2016M. doi:10.1073/pnas.0409512102. PMC 548571. PMID 15684054.