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This review offers the most comprehensive review of the regulation, signaling, and biology of IL-21, including actions within both lymphoid and myeloid cell lineages.
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Annu Rev Immunol
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This article provides the most detailed analysis of signaling via IL-21.
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Zeng R., Spolski R., Casas E., Zhu W., Levy D.E., and Leonard W.J. The molecular basis of IL-21-mediated proliferation. Blood 109 (2007) 4135-4142. This article provides the most detailed analysis of signaling via IL-21.
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Ozaki K., Spolski R., Ettinger R., Kim H.P., Wang G., Qi C.F., Hwu P., Shaffer D.J., Akilesh S., Roopenian D.C., et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol 173 (2004) 5361-5371
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Jin H., Carrio R., Yu A., and Malek T.R. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J Immunol 173 (2004) 657-665
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Ettinger R., Sims G.P., Fairhurst A.M., Robbins R., da Silva Y.S., Spolski R., Leonard W.J., and Lipsky P.E. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J Immunol 175 (2005) 7867-7879
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Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line C (epsilon) transcription of IL-4-stimulated B cells
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Suto A., Nakajima H., Hirose K., Suzuki K., Kagami S., Seto Y., Hoshimoto A., Saito Y., Foster D.C., and Iwamoto I. Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line C (epsilon) transcription of IL-4-stimulated B cells. Blood 100 (2002) 4565-4573
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33845903869
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IL-21-induced Bepsilon cell apoptosis mediated by natural killer T cells suppresses IgE responses
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Harada M., Magara-Koyanagi K., Watarai H., Nagata Y., Ishii Y., Kojo S., Horiguchi S., Okamoto Y., Nakayama T., Suzuki N., et al. IL-21-induced Bepsilon cell apoptosis mediated by natural killer T cells suppresses IgE responses. J Exp Med 203 (2006) 2929-2937
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IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice
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This article illustrates the strong therapeutic potential of IL-21 as a cytokine that can suppress IgE-mediated anaphylaxis and describes this effect as being mediated by the IL-21 induction of Id2, a repressor of IgE class switch recombination.
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Kishida T., Hiromura Y., Shin-Ya M., Asada H., Kuriyama H., Sugai M., Shimizu A., Yokota Y., Hama T., Imanishi J., et al. IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice. J Immunol 179 (2007) 8554-8561. This article illustrates the strong therapeutic potential of IL-21 as a cytokine that can suppress IgE-mediated anaphylaxis and describes this effect as being mediated by the IL-21 induction of Id2, a repressor of IgE class switch recombination.
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Kishida, T.1
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Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells
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Bryant V.L., Ma C.S., Avery D.T., Li Y., Good K.L., Corcoran L.M., de Waal Malefyt R., and Tangye S.G. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. J Immunol 179 (2007) 8180-8190
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Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell-B cell collaboration
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Hiromura Y., Kishida T., Nakano H., Hama T., Imanishi J., Hisa Y., and Mazda O. IL-21 administration into the nostril alleviates murine allergic rhinitis. J Immunol 179 (2007) 7157-7165
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IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo
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Frohlich A., Marsland B.J., Sonderegger I., Kurrer M., Hodge M.R., Harris N.L., and Kopf M. IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. Blood 109 (2007) 2023-2031
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18
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T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells
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Chtanova T., Tangye S.G., Newton R., Frank N., Hodge M.R., Rolph M.S., and Mackay C.R. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J Immunol 173 (2004) 68-78
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19
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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
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Wurster A.L., Rodgers V.L., Satoskar A.R., Whitters M.J., Young D.A., Collins M., and Grusby M.J. 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. J Exp Med 196 (2002) 969-977
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IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways
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Articles 20-22 presented the first evidence for the essential role played by IL-21 in the development and function of the recently described Th17 lineage, including its role in the development of autoimmune pathology in experimental allergic encephalitis.
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Zhou L., Ivanov I.I., Spolski R., Min R., Shenderov K., Egawa T., Levy D.E., Leonard W.J., and Littman D.R. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8 (2007) 967-974. Articles 20-22 presented the first evidence for the essential role played by IL-21 in the development and function of the recently described Th17 lineage, including its role in the development of autoimmune pathology in experimental allergic encephalitis.
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IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells
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Korn T., Bettelli E., Gao W., Awasthi A., Jager A., Strom T.B., Oukka M., and Kuchroo V.K. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448 (2007) 484-487
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Korn, T.1
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Essential autocrine regulation by IL-21 in the generation of inflammatory T cells
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Nurieva R., Yang X.O., Martinez G., Zhang Y., Panopoulos A.D., Ma L., Schluns K., Tian Q., Watowich S.S., Jetten A.M., et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448 (2007) 480-483
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IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production
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Coquet J.M., Kyparissoudis K., Pellicci D.G., Besra G., Berzins S.P., Smyth M.J., and Godfrey D.I. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J Immunol 178 (2007) 2827-2834
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The IL-21 receptor augments Th2 effector function and alternative macrophage activation
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Pesce J., Kaviratne M., Ramalingam T.R., Thompson R.W., Urban Jr. J.F., Cheever A.W., Young D.A., Collins M., Grusby M.J., and Wynn T.A. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest 116 (2006) 2044-2055
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IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of eomesodermin expression
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Suto A., Wurster A.L., Reiner S.L., and Grusby M.J. IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of eomesodermin expression. J Immunol 177 (2006) 3721-3727
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Suto, A.1
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T(H)-17 cells in the circle of immunity and autoimmunity
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Bettelli E., Oukka M., and Kuchroo V.K. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8 (2007) 345-350
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Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells
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Bettelli E., Carrier Y., Gao W., Korn T., Strom T.B., Oukka M., Weiner H.L., and Kuchroo V.K. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441 (2006) 235-238
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The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells
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Ivanov I.I., McKenzie B.S., Zhou L., Tadokoro C.E., Lepelley A., Lafaille J.J., Cua D.J., and Littman D.R. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126 (2006) 1121-1133
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IL-23 drives a pathogenic T cell population that induces autoimmune inflammation
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Langrish C.L., Chen Y., Blumenschein W.M., Mattson J., Basham B., Sedgwick J.D., McClanahan T., Kastelein R.A., and Cua D.J. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201 (2005) 233-240
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IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes
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Peluso I., Fantini M.C., Fina D., Caruso R., Boirivant M., MacDonald T.T., Pallone F., and Monteleone G. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol 178 (2007) 732-739
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IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes
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Li Y., and Yee C. IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes. Blood 111 (2008) 229-235
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Zeng R., Spolski R., Finkelstein S.E., Oh S., Kovanen P.E., Hinrichs C.S., Pise-Masison C.A., Radonovich M.F., Brady J.N., Restifo N.P., et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med 201 (2005) 139-148
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Li Y., Bleakley M., and Yee C. IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response. J Immunol 175 (2005) 2261-2269
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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)
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White L., Krishnan S., Strbo N., Liu H., Kolber M.A., Lichtenheld M.G., Pahwa R.N., and Pahwa S. 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 (2007) 3873-3880
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IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21
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Moroz A., Eppolito C., Li Q., Tao J., Clegg C.H., and Shrikant P.A. 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 (2004) 900-909
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Interleukin 21 therapy increases the density of tumor infiltrating CD8(+)T cells and inhibits the growth of syngeneic tumors
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Sondergaard H., Frederiksen K.S., Thygesen P., Galsgaard E.D., Skak K., Kristjansen P.E., Odum N., and Kragh M. Interleukin 21 therapy increases the density of tumor infiltrating CD8(+)T cells and inhibits the growth of syngeneic tumors. Cancer Immunol Immunother (2007)
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