Interleukin 21

Living reference work entry


Interleukin-21 is a type I cytokine with actions on both lymphoid and myeloid cells. Soon after its discovery, IL-21 was shown to induce cytotoxic activity in both CD8+ T cells and NK cells, leading to the elucidation of its antitumor activity in animal models. This preclinical work led to the inclusion of IL-21 in human clinical trials in patients with advanced solid tumors, including melanoma and renal cell carcinoma. Encouraging results were seen with the use of IL-21 as a single agent, and it is possible that IL-21 might yield enhanced results as a component of combination therapy or in adoptive immunotherapy approaches for the generation of CD8+ T cells with potent antitumor activity.


IL-21 Anti-tumor CD8+ T cells NK cells 



R.S. and W.J.L. are supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and National Institutes of Health.

Conflict of interest statement: R.S. and W.J.L. are inventors on patents and patent applications related to IL-21.


  1. Brady J, Hayakawa Y, Smyth MJ, Nutt SL. IL-21 induces the functional maturation of murine NK cells. J Immunol. 2004;172:2048–58.CrossRefPubMedGoogle Scholar
  2. Brandt K, Bulfone-Paus S, Foster DC, Ruckert R. Interleukin-21 inhibits dendritic cell activation and maturation. Blood. 2003;102:4090–8.CrossRefPubMedGoogle Scholar
  3. Davis ID, Brady B, Kefford RF, Millward M, Cebon J, Skrumsager BK, Mouritzen U, Hansen LT, Skak K, Lundsgaard D, Frederiksen KS, Kristjansen PE, McArthur G. Clinical and biological efficacy of recombinant human interleukin-21 in patients with stage IV malignant melanoma without prior treatment: a phase IIa trial. Clin Cancer Res. 2009;15:2123–9.CrossRefPubMedGoogle Scholar
  4. Frederiksen KS, Lundsgaard D, Freeman JA, Hughes SD, Holm TL, Skrumsager BK, Petri A, Hansen LT, McArthur GA, Davis ID, Skak K. IL-21 induces in vivo immune activation of NK cells and CD8(+) T cells in patients with metastatic melanoma and renal cell carcinoma. Cancer Immunol Immunother. 2008;57:1439–49.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Hashmi MH, Van Veldhuizen PJ. Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma. Expert Opin Biol Ther. 2010;10:807–17.CrossRefPubMedGoogle Scholar
  6. Hinrichs CS, Spolski R, Paulos CM, Gattinoni L, Kerstann KW, Palmer DC, Klebanoff CA, Rosenberg SA, Leonard WJ, Restifo NP. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood. 2008;111:5326–33.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Jin H, Carrio R, Yu A, Malek TR. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J Immunol. 2004;173:657–65.CrossRefPubMedGoogle Scholar
  8. Kasaian MT, Whitters MJ, Carter LL, Lowe LD, Jussif JM, Deng B, Johnson KA, Witek JS, Senices M, Konz RF, Wurster AL, Donaldson DD, Collins M, Young DA, Grusby MJ. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity. 2002;16:559–69.CrossRefPubMedGoogle Scholar
  9. Konforte D, Paige CJ. Identification of cellular intermediates and molecular pathways induced by IL-21 in human B cells. J Immunol. 2006;177:8381–92.CrossRefPubMedGoogle Scholar
  10. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007;448:484–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Markley JC, Sadelain M. IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice. Blood. 2010;115:3508–19.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Moroz A, Eppolito C, Li Q, Tao J, Clegg CH, Shrikant PA. 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. 2004;173:900–9.CrossRefPubMedGoogle Scholar
  13. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993;73:147–57.CrossRefPubMedGoogle Scholar
  14. Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ. Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc Natl Acad Sci U S A. 2000;97:11439–44.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, Morse 3rd HC, Liu C, Schwartzberg PL, Leonard WJ. A critical role for IL-21 in regulating immunoglobulin production. Science. 2002;298:1630–4.CrossRefPubMedGoogle Scholar
  16. Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, Qi CF, Hwu P, Shaffer DJ, Akilesh S, Roopenian DC, Morse 3rd HC, Lipsky PE, Leonard WJ. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol. 2004;173:5361–71.CrossRefPubMedGoogle Scholar
  17. 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. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408:57–63.CrossRefPubMedGoogle Scholar
  18. Pot C, Jin H, Awasthi A, Liu SM, Lai CY, Madan R, Sharpe AH, Karp CL, Miaw SC, Ho IC, Kuchroo VK. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol. 2009;183:797–801.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Skak K, Kragh M, Hausman D, Smyth MJ, Sivakumar PV. Interleukin 21: combination strategies for cancer therapy. Nat Rev Drug Discov. 2008;7:231–40.CrossRefPubMedGoogle Scholar
  20. Skak K, Sondergaard H, Frederiksen KS, Ehrnrooth E. In vivo antitumor efficacy of interleukin-21 in combination with chemotherapeutics. Cytokine. 2009;48:231–8.CrossRefPubMedGoogle Scholar
  21. Sondergaard H, Coquet JM, Uldrich AP, McLaughlin N, Godfrey DI, Sivakumar PV, Skak K, Smyth MJ. Endogenous IL-21 restricts CD8+ T cell expansion and is not required for tumor immunity. J Immunol. 2009;183:7326–36.CrossRefPubMedGoogle Scholar
  22. Sondergaard H, Galsgaard ED, Bartholomaeussen M, Straten PT, Odum N, Skak K. Intratumoral interleukin-21 increases antitumor immunity, tumor-infiltrating CD8+ T-cell density and activity, and enlarges draining lymph nodes. J Immunother. 2010;33:236–49.CrossRefPubMedGoogle Scholar
  23. Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol. 2008;26:57–79.CrossRefPubMedGoogle Scholar
  24. Spolski R, Leonard WJ. IL-21 is an immune activator that also mediates suppression via IL-10. Crit Rev Immunol. 2010;30:559–70.CrossRefPubMedGoogle Scholar
  25. Steele N, Anthony A, Saunders M, Esmarck B, Ehrnrooth E, Kristjansen PE, Nihlen A, Hansen LT, Cassidy J. A phase 1 trial of recombinant human IL-21 in combination with cetuximab in patients with metastatic colorectal cancer. Br J Cancer. 2012;106:793–8.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Wang G, Tschoi M, Spolski R, Lou Y, Ozaki K, Feng C, Kim G, Leonard WJ, Hwu P. In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res. 2003;63:9016–22.PubMedGoogle Scholar
  27. Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, Pise-Masison CA, Radonovich MF, Brady JN, Restifo NP, Berzofsky JA, Leonard WJ. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med. 2005;201:139–48.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Zeng R, Spolski R, Casas E, Zhu W, Levy DE, Leonard WJ. The molecular basis of IL-21-mediated proliferation. Blood. 2007;109:4135–42.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8:967–74.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Laboratory of Molecular ImmunologyNational Heart, Lung, and Blood InstituteBethesdaUSA

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