Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation (original) (raw)
Leonard, W. J. in Fundamental Immunology 5th Edn (ed. Paul, W. E.) 701–747 (Lippincott Williams & Wilkins, Philadelphia, 2003) Google Scholar
Leonard, W. J. Cytokines and immunodeficiency diseases. Nature Rev. Immunol.1, 200–208 (2001). CAS Google Scholar
Noguchi, M. et al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell73, 147–157 (1993). CASPubMed Google Scholar
Russell, S. M. et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science270, 797–800 (1995). CASPubMed Google Scholar
Macchi, P. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature377, 65–68 (1995). CASPubMed Google Scholar
Ozaki, K., Kikly, K., Michalovich, D., Young, P. R. & Leonard, W. J. Cloning of a type I cytokine receptor most related to the IL-2 receptor β chain. Proc. Natl Acad. Sci. USA97, 11439–11444 (2000). This was the first report to identify the IL-21 receptor as a novel type I cytokine receptor and to describe its structural features and signal-transduction pathways. CASPubMedPubMed Central Google Scholar
Parrish-Novak, J. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature408, 57–63 (2000). This paper identifies the IL-21 receptor and its ligand and presents the first analysis of the proliferative and functional effects of IL-21 on T cells, B cells and NK cells. CASPubMed Google Scholar
Asao, H. et al. The common γ-chain is an indispensable subunit of the IL-21 receptor complex. J. Immunol.167, 1–5 (2001). CASPubMed Google Scholar
Habib, T., Senadheera, S., Weinberg, K. & Kaushansky, K. The common γ chain (γc) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3. Biochemistry41, 8725–8731 (2002). CASPubMed Google Scholar
Bennett, F. et al. Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. J. Immunol.170, 711–718 (2003). CASPubMed Google Scholar
Strengell, M., Sareneva, T., Foster, D., Julkunen, I. & Matikainen, S. IL-21 up-regulates the expression of genes associated with innate immunity and TH1 response. J. Immunol.169, 3600–3605 (2002). PubMed Google Scholar
Strengell, M. et al. IL-21 in synergy with IL-15 or IL-18 enhances IFN-γ production in human NK and T cells. J. Immunol.170, 5464–5469 (2003). CASPubMed Google Scholar
Lin, J. -X. et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity2, 331–339 (1995). CASPubMed Google Scholar
Lin, J. -X., Mietz, J., Modi, W. S., John, S. & Leonard, W. J. Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells. J. Biol. Chem.271, 10738–10744 (1996). CASPubMed Google Scholar
Hou, J. et al. An interleukin-4-induced transcription factor: IL-4 Stat. Science265, 1701–1706 (1994). CASPubMed Google Scholar
Quelle, F. W. et al. Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol. Cell. Biol.15, 3336–3343 (1995). CASPubMedPubMed Central Google Scholar
Nielsen, M., Svejgaard, A., Skov, S. & Odum, N. Interleukin-2 induces tyrosine phosphorylation and nuclear translocation of stat3 in human T lymphocytes. Eur. J. Immunol.24, 3082–3086 (1994). CASPubMed Google Scholar
Chin, Y. E., Kitagawa, M., Kuida, K., Flavell, R. A. & Fu, X. Y. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol. Cell. Biol.17, 5328–5337 (1997). CASPubMedPubMed Central Google Scholar
Yu, C. L. et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science269, 81–83 (1995). CASPubMed Google Scholar
Bromberg, J. & Darnell, J. E. Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene19, 2468–2473 (2000). CASPubMed Google Scholar
Jin, H., Carrio, R., Yu, A. & Malek, T. R. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J. Immunol.173, 657–665 (2004). This paper describes the context-dependent effects of IL-21 on the B-cell lineage and identifies a BIM-dependent, IL-21-mediated apoptotic pathway in T-cell-independent B-cell responses. CASPubMed Google Scholar
Brandt, K., Bulfone-Paus, S., Foster, D. C. & Ruckert, R. Interleukin-21 inhibits dendritic cell activation and maturation. Blood102, 4090–4098 (2003). CASPubMed Google Scholar
Brandt, K. et al. Interleukin-21 inhibits dendritic cell-mediated T cell activation and induction of contact hypersensitivity in vivo. J. Invest. Dermatol.121, 1379–1382 (2003). CASPubMed Google Scholar
Distler, J. H. et al. Expression of interleukin-21 receptor in epidermis from patients with systemic sclerosis. Arthritis Rheum.52, 856–864 (2005). CASPubMed Google Scholar
Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science298, 1630–1634 (2002). This paper describes the defective antibody production inIl21r−/−mice and shows that IL-21 and IL-4 cooperate in the regulation of antibody production. CASPubMed Google Scholar
Eberl, M., Engel, R., Beck, E. & Jomaa, H. Differentiation of human γδ T cells towards distinct memory phenotypes. Cell. Immunol.218, 1–6 (2002). CASPubMed Google Scholar
Strengell, M., Julkunen, I. & Matikainen, S. IFN-α regulates IL-21 and IL-21R expression in human NK and T cells. J. Leukoc. Biol.76, 416–422 (2004). CASPubMed Google Scholar
Zeng, R. et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J. Exp. Med.201, 139–148 (2005). This report describes the cooperative effect of IL-21 and IL-15 on CD8+ T-cell proliferation and antitumour activity towards established melanomas. CASPubMedPubMed Central Google Scholar
Chtanova, T. et al. 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, 68–78 (2004). CASPubMed Google Scholar
Wurster, A. L. et al. Interleukin 21 is a T helper (TH) cell 2 cytokine that specifically inhibits the differentiation of naive TH cells into interferon γ-producing TH1 cells. J. Exp. Med.196, 969–977 (2002). CASPubMedPubMed Central Google Scholar
Kim, H. -P., Korn, L. L., Gamero, A. M. & Leonard, W. J. Calcium-dependent activation of interleukin-21 gene expression in T cells. J. Biol. Chem.280, 25291–25297 (2005). CASPubMed Google Scholar
Mehta, D. S., Wurster, A. L., Weinmann, A. S. & Grusby, M. J. NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proc. Natl Acad. Sci. USA102, 2016–2021 (2005). CASPubMedPubMed Central Google Scholar
Kasaian, M. T. et al. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity16, 559–569 (2002). CASPubMed Google Scholar
Kuhn, R., Rajewsky, K. & Muller, W. Generation and analysis of interleukin-4 deficient mice. Science254, 707–710 (1991). CASPubMed Google Scholar
Suto, A. et al. Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line Cε transcription of IL-4-stimulated B cells. Blood100, 4565–4573 (2002). CASPubMed Google Scholar
Oettgen, H. C. Regulation of the IgE isotype switch: new insights on cytokine signals and the functions of ε germline transcripts. Curr. Opin. Immunol.12, 618–623 (2000). CASPubMed Google Scholar
Kaplan, M. H., Schindler, U., Smiley, S. T. & Grusby, M. J. Stat6 is required for mediating responses to IL-4 and for development of TH2 cells. Immunity4, 313–319 (1996). CASPubMed Google Scholar
Cao, X. et al. Characterization of cDNAs encoding the murine interleukin 2 receptor (IL-2R) γ chain: chromosomal mapping and tissue specificity of IL-2R γ chain expression. Proc. Natl Acad. Sci. USA90, 8464–8468 (1993). CASPubMedPubMed Central Google Scholar
DiSanto, J. P., Rieux-Laucat, F., Dautry-Varsat, A., Fischer, A. & de Saint Basile, G. Defective human interleukin 2 receptor γ chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells. Proc. Natl Acad. Sci. USA91, 9466–9470 (1994). CASPubMedPubMed Central Google Scholar
Puel, A., Ziegler, S. F., Buckley, R. H. & Leonard, W. J. Defective IL7R expression in T−B+NK+ severe combined immunodeficiency. Nature Genet.20, 394–397 (1998). CASPubMed Google Scholar
Waldmann, T. A. The multi-subunit interleukin-2 receptor. Annu. Rev. Biochem.58, 875–911 (1989). CASPubMed Google Scholar
Conley, M. E. et al. Nonrandom X chromosome inactivation in B cells from carriers of X chromosome-linked severe combined immunodeficiency. Proc. Natl Acad. Sci. USA85, 3090–3094 (1988). CASPubMedPubMed Central Google Scholar
Akashi, K., Kondo, M., von Freeden-Jeffry, U., Murray, R. & Weissman, I. L. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell89, 1033–1041 (1997). CASPubMed Google Scholar
Otani, H., Erdos, M. & Leonard, W. J. Tyrosine kinase(s) regulate apoptosis and bcl-2 expression in a growth factor-dependent cell line. J. Biol. Chem.268, 22733–22736 (1993). CASPubMed Google Scholar
Mehta, D. S. et al. IL-21 induces the apoptosis of resting and activated primary B cells. J. Immunol.170, 4111–4118 (2003). CASPubMed Google Scholar
Ozaki, K. 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, 5361–5371 (2004). This report shows that IL-21 initiates the development of B cells into plasma cells through directly inducing expression of the master regulator of this process, BLIMP1. CASPubMed Google Scholar
Lenardo, M. et al. Mature T lymphocyte apoptosis — immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol.17, 221–253 (1999). CASPubMed Google Scholar
Refaeli, Y., Van Parijs, L., London, C. A., Tschopp, J. & Abbas, A. K. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity8, 615–623 (1998). CASPubMed Google Scholar
Pene, J. et al. IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J. Immunol.172, 5154–5157 (2004). CASPubMed Google Scholar
Calame, K. L., Lin, K. I. & Tunyaplin, C. Regulatory mechanisms that determine the development and function of plasma cells. Annu. Rev. Immunol.21, 205–230 (2003). CASPubMed Google Scholar
Shaffer, A. L. et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity17, 51–62 (2002). CASPubMed Google Scholar
Murphy, E. D. & Roths, J. B. A Y chromosome associated factor in strain BXSB producing accelerated autoimmunity and lymphoproliferation. Arthritis Rheum.22, 1188–1194 (1979). CASPubMed Google Scholar
Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity2, 223–238 (1995). CASPubMed Google Scholar
DiSanto, J. P., Muller, W., Guy-Grand, D., Fischer, A. & Rajewsky, K. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor γ chain. Proc. Natl Acad. Sci. USA92, 377–381 (1995). CASPubMedPubMed Central Google Scholar
Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science268, 1472–1476 (1995). CASPubMed Google Scholar
Lodolce, J. P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity9, 669–676 (1998). CASPubMed Google Scholar
Kennedy, M. K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med.191, 771–780 (2000). CASPubMedPubMed Central Google Scholar
Sivori, S. et al. IL-21 induces both rapid maturation of human CD34+ cell precursors towards NK cells and acquisition of surface killer Ig-like receptors. Eur. J. Immunol.33, 3439–3447 (2003). CASPubMed Google Scholar
Sivori, S. et al. Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation. Proc. Natl Acad. Sci. USA99, 4526–4531 (2002). CASPubMedPubMed Central Google Scholar
Vosshenrich, C. A. et al. Roles for common cytokine receptor γ-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo. J. Immunol.174, 1213–1221 (2005). CASPubMed Google Scholar
Toomey, J. A., Gays, F., Foster, D. & Brooks, C. G. Cytokine requirements for the growth and development of mouse NK cells in vitro. J. Leukoc. Biol.74, 233–242 (2003). CASPubMed Google Scholar
Brady, J., Hayakawa, Y., Smyth, M. J. & Nutt, S. L. IL-21 induces the functional maturation of murine NK cells. J. Immunol.172, 2048–2058 (2004). CASPubMed Google Scholar
Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nature Immunol.1, 426–432 (2000). CAS Google Scholar
Zhang, X., Sun, S., Hwang, I., Tough, D. F. & Sprent, J. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity8, 591–599 (1998). CASPubMed Google Scholar
Andrade, F. et al. Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis. Immunity8, 451–460 (1998). CASPubMed Google Scholar
Wang, G. et al. In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res.63, 9016–9022 (2003). CASPubMed Google Scholar
Pelletier, M., Bouchard, A. & Girard, D. In vivo and in vitro roles of IL-21 in inflammation. J. Immunol.173, 7521–7530 (2004). CASPubMed Google Scholar
Anderson, M. S. & Bluestone, J. A. The NOD mouse: a model of immune dysregulation. Annu. Rev. Immunol.23, 447–485 (2005). CASPubMed Google Scholar
Denny, P. et al. Mapping of the IDDM locus Idd3 to a 0.35-cM interval containing the interleukin-2 gene. Diabetes46, 695–700 (1997). CASPubMed Google Scholar
King, C., Ilic, A., Koelsch, K. & Sarvetnick, N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell117, 265–277 (2004). CASPubMed Google Scholar
Vollmer, T. L. et al. Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen. J. Immunol.174, 2696–2701 (2005). CASPubMed Google Scholar
Overwijk, W. W. et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J. Exp. Med.198, 569–580 (2003). CASPubMedPubMed Central Google Scholar
Klebanoff, C. A. et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc. Natl Acad. Sci. USA101, 1969–1974 (2004). CASPubMedPubMed Central Google Scholar
Ugai, S. et al. Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts. Cancer Gene Ther.10, 187–192 (2003). CASPubMed Google Scholar
Ugai, S. et al. Transduction of the IL-21 and IL-23 genes in human pancreatic carcinoma cells produces natural killer cell-dependent and -independent antitumor effects. Cancer Gene Ther.10, 771–778 (2003). CASPubMed Google Scholar
Ma, H. L. et al. IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-γ. J. Immunol.171, 608–615 (2003). CASPubMed Google Scholar
Di Carlo, E. et al. IL-21 induces tumor rejection by specific CTL and IFN-γ-dependent CXC chemokines in syngeneic mice. J. Immunol.172, 1540–1547 (2004). CASPubMed Google Scholar
Moroz, A. et al. 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, 900–909 (2004). This paper describes the unique ability of IL-21 to induce long-term immunity to tumours through its anti-apoptotic and survival effects on CD8+ T cells. CASPubMed Google Scholar
Shrikant, P. & Mescher, M. F. Opposing effects of IL-2 in tumor immunotherapy: promoting CD8 T cell growth and inducing apoptosis. J. Immunol.169, 1753–1759 (2002). CASPubMed Google Scholar
Kishida, T. et al. Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic lymphoma. Mol. Ther.8, 552–558 (2003). CASPubMed Google Scholar
Schorle, H. et al. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature352, 621–624 (1991). CASPubMed Google Scholar
Kundig, T. M. et al. Immune responses in interleukin-2 deficient mice. Science262, 1059–1061 (1993). CASPubMed Google Scholar
Sadlack, B., et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell75, 253–261 (1993). CASPubMed Google Scholar
Kopf, M., et al. Disruption of the murine IL-4 gene blocks TH2 cytokine responses. Nature362, 245–248 (1993). CASPubMed Google Scholar
von Freeden-Jeffry, U. et al. Lymphopenia in interleukin-7 deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med.181, 1519–1526 (1995). CASPubMed Google Scholar
Townsend, J. M. et al. IL-9 deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity13, 573–583 (2000). CASPubMed Google Scholar
McKenzie, G. J. et al. Impaired development of TH2 cells in IL-13 deficient mice. Immunity9, 423–432 (1998). CASPubMed Google Scholar
Willerford, D. M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity3, 521–530 (1995). CASPubMed Google Scholar
Roifman, C. M. Human IL-2 receptor α chain deficiency. Pediatr. Res.48, 6–11 (2000). CASPubMed Google Scholar
Noben-Trauth, N. et al. An IL-4 independent pathway for CD4+ T cell IL-4 production revealed in IL-4 receptor deficient mice. Proc. Natl Acad. Sci. USA94, 10838–10843 (1997). CASPubMedPubMed Central Google Scholar
Peschon, J. et al. Early lymphocyte expansion is severely impaired in interleukin-7 receptor deficient mice. J. Exp. Med.180, 1955–1960 (1994). CASPubMed Google Scholar