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PMID: 19234181 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

IL-21 mediates suppressive effects via its induction of IL-10.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 182 ·No. 5 ·2009-03-01 ·Pages 2859-67

Spolski R, Kim HP, Zhu W, Levy DE, Leonard WJ

Abstract

IL-21 is a pleiotropic cytokine that is required for normal Ig production. We previously showed that IL-21 was elevated in BXSB-Yaa mice with systemic lupus erythematosus. These mice also had elevated IL-10 levels, and we now show that IL-21 induces IL-10 mRNA and protein, suggesting unexpected immunosuppressive activities for IL-21. Indeed, Th1 priming with IL-21 leads to accumulation of cells with immunosuppressive activity, and IL-21 overexpression decreases specific Ab production after immunization in an IL-10-dependent fashion. Moreover, we show that IL-21 signaling is required for maximal induction of IL-10 by IL-6 or IL-27. Overall, our data indicate that IL-21 regulates immune responses at least in part by inducing IL-10 and reveal unanticipated immunosuppressive actions for this cytokine.

MeSH Terms
Animals Cell Aggregation/immunology Cell Line Coculture Techniques Down-Regulation/genetics,immunology Humans Immunosuppression Therapy Interleukin-10/biosynthesis,deficiency,genetics Interleukins/genetics,physiology Lymphocyte Activation/genetics,immunology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Th1 Cells/immunology,metabolism Transcriptional Activation/immunology
Chemicals
Interleukins Interleukin-10 interleukin-21
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Spolski Rosanne
Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Kim Hyoung-Pyo
Zhu Wei
Levy David E
Leonard Warren J
References (56)
56 references, click to expand
  1. Functional analysis of the interaction of the antigen-specific T cell receptor with its ligands.
    J Immunol. 1986 Feb 1;136(3):757-68 PMID: 2416829
  2. 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 Jul 15;173(2):900-9 PMID: 15240677
  3. Cutting edge: IL-21 is not essential for Th17 differentiation or experimental autoimmune encephalomyelitis.
    J Immunol. 2008 Jun 1;180(11):7097-101 PMID: 18490706
  4. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells.
    J Immunol. 2005 Dec 15;175(12):7867-79 PMID: 16339522
  5. IL-17 family cytokines and the expanding diversity of effector T cell lineages.
    Annu Rev Immunol. 2007;25:821-52 PMID: 17201677
  6. Interleukin-10 and the interleukin-10 receptor.
    Annu Rev Immunol. 2001;19:683-765 PMID: 11244051
  7. Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21.
    J Immunol. 2006 Oct 15;177(8):5236-47 PMID: 17015709
  8. Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10:interferon-gamma-secreting cells in the peripheral blood.
    Arthritis Rheum. 1996 Mar;39(3):379-85 PMID: 8607886
  9. Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.
    J Exp Med. 2007 Feb 19;204(2):273-83 PMID: 17283209
  10. A fundamental role for interleukin-21 in the generation of T follicular helper cells.
    Immunity. 2008 Jul 18;29(1):127-37 PMID: 18602282
  11. IL-21 and IL-21R are not required for development of Th17 cells and autoimmunity in vivo.
    Eur J Immunol. 2008 Jul;38(7):1833-8 PMID: 18546146
  12. STAT-3 activation is required for normal G-CSF-dependent proliferation and granulocytic differentiation.
    Immunity. 2001 Feb;14(2):193-204 PMID: 11239451
  13. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages.
    Immunity. 2008 Jul 18;29(1):138-49 PMID: 18599325
  14. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans.
    Cell. 1993 Apr 9;73(1):147-57 PMID: 8462096
  15. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression.
    J Immunol. 2007 Mar 15;178(6):3822-30 PMID: 17339481
  16. Interleukin-21 inhibits dendritic cell activation and maturation.
    Blood. 2003 Dec 1;102(12):4090-8 PMID: 12893770
  17. Development and characterization of IL-21-producing CD4+ T cells.
    J Exp Med. 2008 Jun 9;205(6):1369-79 PMID: 18474630
  18. IL-10 interrupts memory B cell expansion in the germinal center by inducing differentiation into plasma cells.
    Eur J Immunol. 1998 Feb;28(2):508-15 PMID: 9521060
  19. Interleukin-10 and related cytokines and receptors.
    Annu Rev Immunol. 2004;22:929-79 PMID: 15032600
  20. The molecular basis of IL-21-mediated proliferation.
    Blood. 2007 May 15;109(10):4135-42 PMID: 17234735
  21. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.
    Nat Immunol. 2007 Sep;8(9):967-74 PMID: 17581537
  22. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis.
    J Immunol. 2004 Jul 1;173(1):657-65 PMID: 15210829
  23. IL-10 regulation of lupus in the NZM2410 murine model.
    Lab Invest. 2006 Nov;86(11):1136-48 PMID: 16924244
  24. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.
    Nat Immunol. 2007 Dec;8(12):1390-7 PMID: 17994024
  25. A critical role for IL-21 in regulating immunoglobulin production.
    Science. 2002 Nov 22;298(5598):1630-4 PMID: 12446913
  26. The IL-21 receptor augments Th2 effector function and alternative macrophage activation.
    J Clin Invest. 2006 Jul;116(7):2044-55 PMID: 16778988
  27. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells.
    Nat Immunol. 2007 Dec;8(12):1372-9 PMID: 17994023
  28. IL-10 regulates murine lupus.
    J Immunol. 2002 Aug 15;169(4):2148-55 PMID: 12165544
  29. The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3.
    Biochemistry. 2002 Jul 9;41(27):8725-31 PMID: 12093291
  30. 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. 2002 Oct 7;196(7):969-77 PMID: 12370258
  31. IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice.
    J Immunol. 2004 Feb 1;172(3):1540-7 PMID: 14734732
  32. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10.
    Nat Immunol. 2007 Dec;8(12):1363-71 PMID: 17994025
  33. Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain.
    Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11439-44 PMID: 11016959
  34. CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis.
    J Exp Med. 2007 Feb 19;204(2):285-97 PMID: 17283207
  35. The role of IL-21 in regulating B-cell function in health and disease.
    Immunol Rev. 2008 Jun;223:60-86 PMID: 18613830
  36. Priming in the presence of IL-10 results in direct enhancement of CD8+ T cell primary responses and inhibition of secondary responses.
    J Immunol. 2005 May 1;174(9):5382-9 PMID: 15843536
  37. Chromatin-level regulation of the IL10 gene in T cells.
    J Biol Chem. 2004 Nov 5;279(45):46818-25 PMID: 15319439
  38. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation.
    Immunity. 2002 Jul;17(1):63-72 PMID: 12150892
  39. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.
    Nature. 2000 Nov 2;408(6808):57-63 PMID: 11081504
  40. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6.
    J Immunol. 2004 Nov 1;173(9):5361-71 PMID: 15494482
  41. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.
    Annu Rev Immunol. 1989;7:145-73 PMID: 2523712
  42. Elevated interleukin-10 levels correlated with disease activity in systemic lupus erythematosus.
    Clin Exp Rheumatol. 1998 May-Jun;16(3):283-8 PMID: 9631750
  43. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.
    Nature. 2007 Jul 26;448(7152):484-487 PMID: 17581588
  44. IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma.
    J Immunol. 2003 Jul 15;171(2):608-15 PMID: 12847225
  45. Regulatory T cells and mechanisms of immune system control.
    Nat Med. 2004 Aug;10(8):801-5 PMID: 15286781
  46. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function.
    J Exp Med. 2005 Jan 3;201(1):139-48 PMID: 15630141
  47. Cytokines and immunodeficiency diseases.
    Nat Rev Immunol. 2001 Dec;1(3):200-8 PMID: 11905829
  48. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells.
    Nat Immunol. 2007 Dec;8(12):1380-9 PMID: 17994022
  49. Interleukin-21: basic biology and implications for cancer and autoimmunity.
    Annu Rev Immunol. 2008;26:57-79 PMID: 17953510
  50. 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. 2004 Jul 1;173(1):68-78 PMID: 15210760
  51. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation.
    Nat Rev Immunol. 2005 Sep;5(9):688-98 PMID: 16138102
  52. In vivo antitumor activity of interleukin 21 mediated by natural killer cells.
    Cancer Res. 2003 Dec 15;63(24):9016-22 PMID: 14695220
  53. Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex.
    J Immunol. 2001 Jul 1;167(1):1-5 PMID: 11418623
  54. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells.
    Nature. 2007 Jul 26;448(7152):480-3 PMID: 17581589
  55. IL-21 induces the functional maturation of murine NK cells.
    J Immunol. 2004 Feb 15;172(4):2048-58 PMID: 14764669
  56. IL-21 induces the apoptosis of resting and activated primary B cells.
    J Immunol. 2003 Apr 15;170(8):4111-8 PMID: 12682241
Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.0802978
Published
2009-03-01
Pages
2859-67
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC2756221
Subset
IM
Grants
NIAID NIH HHS · R01 AI028900 · United States
Intramural NIH HHS · Z99 HL999999 · United States
NIAID NIH HHS · AI28900 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.0802978 PMC Full Text View journal details
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