Interleukin-21: A modulator of lymphoid proliferation, apoptosis and differentiation

Nature Reviews Immunology

Volumn 5, Issue 9, 2005, Pages 688-698

  Leonard, Warren J ^a   Spolski, Rosanne ^a  

^a NATIONAL HEART LUNG AND BLOOD INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKINE RECEPTOR; INTERLEUKIN 15; INTERLEUKIN 21; INTERLEUKIN 21 RECEPTOR; INTERLEUKIN 4; RECEPTOR SUBUNIT; INTERLEUKIN DERIVATIVE;

ALLERGY; ANTIBODY PRODUCTION; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ASTHMA; AUTOIMMUNE DISEASE; AUTOIMMUNITY; B LYMPHOCYTE; CELL DIFFERENTIATION; CELL FUNCTION; CELL GROWTH; CELL PROLIFERATION; COMBINED IMMUNODEFICIENCY; DENDRITIC CELL; EVOLUTIONARY HOMOLOGY; IMMUNE RESPONSE; LYMPHOID CELL; MEMORY CELL; MUTATION; NATURAL KILLER CELL; NONHUMAN; PLASMA CELL; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE; TUMOR; ANIMAL; CYTOLOGY; HUMAN; IMMUNOLOGY; LYMPHOCYTE; PHYSIOLOGY;

ANIMALS; APOPTOSIS; CELL DIFFERENTIATION; HUMANS; INTERLEUKINS; LYMPHOCYTES;

EID: 25444434157     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri1688     Document Type: Review

References (93)

1. Leonard, W. J. in Fundamental Immunology 5th Edn (ed. Paul, W. E.) 701-747 (Lippincott Williams & Wilkins, Philadelphia, 2003)
2. Leonard, W. J. Cytokines and immunodeficiency diseases. Nature Rev. Immunol. 1, 200-208 (2001).
3. Noguchi, M. et al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73, 147-157 (1993).
4. Russell, S. M. et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270, 797-800 (1995).
5. Macchi, P. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377, 65-68 (1995).
6. 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. USA 97, 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-to ansduction pathways.
7. Parrish-Novak, J. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 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.
8. Asao, H. et al. The common γ-chain is an indispensable subunit of the IL-21 receptor complex. J. Immunol. 167, 1-5 (2001).
9. c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3. Biochemistry 41, 8725-8731 (2002).
10. 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).
11. H1 response. J. Immunol. 169, 3600-3605 (2002).
12. 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).
13. 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. Immunity 2, 331-339 (1995).
14. 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).
15. Hou, J. et al. An interleukin-4-induced transcription factor: IL-4 Stat. Science 265, 1701-1706 (1994).
16. 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).
17. 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).
18. 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).
19. Stephanou, A. & Latchman, D. S. STAT-1: a novel regulator of apoptosis. Int. J. Exp. Pathol. 84, 239-244 (2003).
20. Yu, C. L. et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269, 81-83 (1995).
21. Bromberg, J. F. et al. Stat3 as an oncogene. Cell 98, 295-303 (1999).
22. Bromberg, J. & Darnell, J. E. Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468-2473 (2000).
23. 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.
24. Brandt, K., Bulfone-Paus, S., Foster, D. C. & Ruckert, R. Interleukin-21 inhibits dendritic cell activation and maturation. Blood 102, 4090-4098 (2003).
25. 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).
26. Distler, J. H. et al. Expression of interleukin-21 receptor in epidermis from patients with systemic sclerosis. Arthritis Rheum. 52, 856-864 (2005).
27. -|- mice and shows that IL-21 and IL-4 cooperate in the regulation of antibody production.
28. Eberl, M., Engel, R., Beck, E. & Jomaa, H. Differentiation of human γδ T cells towards distinct memory phenotypes. Cell. Immunol. 218, 1-6 (2002).
29. 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).
30. + T-cell proliferation and antitumour activity towards established melanomas.
31. H2 effector cells that provide help for B cells. J. Immunol. 173, 68-78 (2004).
32. H1 cells. J. Exp. Med. 196, 969-977 (2002).
33. 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).
34. 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. USA 102, 2016-2021 (2005).
35. 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. Immunity 16, 559-569 (2002).
36. Kuhn, R., Rajewsky, K. & Muller, W. Generation and analysis of interleukin-4 deficient mice. Science 254, 707-710 (1991).
37. Suto, A. et al. Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line Cε transcription of IL-4-stimulated B cells. Blood 100, 4565-4573 (2002).
38. 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).
39. H2 cells. Immunity 4, 313-319 (1996).
40. 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. USA 90, 8464-8468 (1993).
41. 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. USA 91, 9466-9470 (1994).
42. + severe combined immunodeficiency. Nature Genet. 20, 394-397 (1998).
43. Waldmann, T. A. The multi-subunit interleukin-2 receptor. Annu. Rev. Biochem. 58, 875-911 (1989).
44. 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. USA 85, 3090-3094 (1988).
45. Akashi, K., Kondo, M., von Freeden-Jeffry, U., Murray, R. & Weissman, I. L. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell 89, 1033-1041 (1997).
46. 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).
47. Mehta, D. S. et al. IL-21 induces the apoptosis of resting and activated primary B cells. J. Immunol. 170, 4111-4118 (2003).
48. 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.
49. Lenardo, M. et al. Mature T lymphocyte apoptosis - immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221-253 (1999).
50. Refaeli, Y., Van Parijs, L., London, C. A., Tschopp, J. & Abbas, A. K. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8, 615-623 (1998).
51. 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).
52. 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).
53. Shaffer, A. L. et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17, 51-62 (2002).
54. 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).
55. Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity 2, 223-238 (1995).
56. 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. USA 92, 377-381 (1995).
57. Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 268, 1472-1476 (1995).
58. Lodolce, J. P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669-676 (1998).
59. 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).
60. + cell precursors towards NK cells and acquisition of surface killer Ig-like receptors. Eur. J. Immunol. 33, 3439-3447 (2003).
61. 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. USA 99, 4526-1531 (2002).
62. 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).
63. 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).
64. 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).
65. 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).
66. + T cells in vivo by IL-15. Immunity 8, 591-599 (1998).
67. Andrade, F. et al. Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis. Immunity 8, 451-460 (1998).
68. Wang, G. et al. In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res. 63, 9016-9022 (2003).
69. Pelletier, M., Bouchard, A. & Girard, D. In vivo and in vitro roles of IL-21 in inflammation. J. Immunol. 173, 7521-7530 (2004).
70. Anderson, M. S. & Bluestone, J. A. The NOD mouse: a model of immune dysregulation. Annu. Rev. Immunol. 23, 447-485 (2005).
71. Denny, P. et al. Mapping of the IDDM locus Idd3 to a 0.35-cM interval containing the interleukin-2 gene. Diabetes 46, 695-700 (1997).
72. King, C., Ilic, A., Koelsch, K. & Sarvetnick, N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117, 265-277 (2004).
73. Vollmer, T. L. et al. Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen. J. Immunol. 174, 2696-2701 (2005).
74. + T cells. J. Exp. Med. 198, 569-580 (2003).
75. + T cells. Proc. Natl Acad. Sci. USA 101, 1969-1974 (2004).
76. 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).
77. 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).
78. 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).
79. 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).
80. + T cells.
81. 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).
82. 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).
83. Schorle, H. et al. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352, 621-624 (1991).
84. Kundig, T. M. et al. Immune responses in interleukin-2 deficient mice. Science 262, 1059-1061 (1993).
85. Sadlack, B., et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253-261 (1993).
86. H2 cytokine responses. Nature 362, 245-248 (1993).
87. von Freed en-Jeffry, U. et al. Lymphopenia in interleukin-7 deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519-1526 (1995).
88. 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. Immunity 13, 573-583 (2000).
89. McKenzie, G. J. et al. Impaired development of TH2 cells in IL-13 deficient mice. Immunity 9, 423-432 (1998).
90. Willerford, D. M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521-530 (1995).
91. Roifman, C. M. Human IL-2 receptor α chain deficiency. Pediatr. Res. 48, 6-11 (2000).
92. + T cell IL-4 production revealed in IL-4 receptor deficient mice. Proc. Natl Acad. Sci. USA 94, 10838-10843 (1997).
93. Peschon, J. et al. Early lymphocyte expansion is severely impaired in interleukin-7 receptor deficient mice. J. Exp. Med. 180, 1955-1960 (1994).