title: Interleukin (IL)-21-independent pathogen-specific CD8+ T-cell expansion, and IL-21-dependent suppression of CD4+ T-cell IL-17 production.
abstract: Although interleukin-21 (IL-21) potently activates and controls the differentiation of immune cells after stimulation in vitro, the role for this pleiotropic cytokine during in vivo infection remains poorly defined. Herein, the requirement for IL-21 in innate and adaptive host defence after Listeria monocytogenes infection was examined. In the innate phase, IL-21 deficiency did not cause significant defects in infection susceptibility, or in the early activation of natural killer and T cells. In the adaptive phase, L. monocytogenes-specific CD8(+) T cells expand to a similar magnitude in IL-21-deficient mice compared with control mice. Interestingly, the IL-21-independent expansion of L. monocytogenes-specific CD8(+) T cells was maintained even in the combined absence of IL-12 and type I interferon (IFN) receptor. Similarly, L. monocytogenes-specific CD4(+) T cells expanded and produced similar levels of IFN-γ regardless of IL-21 deficiency. Unexpectedly however, IL-21 deficiency caused significantly increased CD4(+) T-cell IL-17 production, and this effect became even more pronounced after L. monocytogenes infection in mice with combined defects in both IL-12 and type I IFN receptor that develop a T helper type 17-dominated CD4(+) T-cell response. Despite increased CD4(+) T-cell IL-17 production, L. monocytogenes-specific T cells re-expanded and conferred protection against secondary challenge with virulent L. monocytogenes regardless of IL-21 deficiency, or combined defects in IL-21, IL-12, and type I IFN receptor. Together, these results demonstrate non-essential individual and combined roles for IL-21, IL-12 and type I IFNs in priming pathogen-specific CD8(+) T cells, and reveal IL-21-dependent suppression of IL-17 production by CD4(+) T cells during in vivo infection.
authors.affiliation: Department of Pediatrics, Center for Infectious Disease and Microbiology Translational Research, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Ertelt
authors.forename: Tanner M
authors.initials: TM
authors.lastname: Johanns
authors.forename: Jared H
authors.initials: JH
authors.lastname: Rowe
authors.forename: Sing Sing
authors.initials: SS
authors.lastname: Way
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D007109:Immunity / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000378:metabolism; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000401:mortality; D008099:Liver / Q000382:microbiology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D013154:Spleen / Q000382:microbiology; D000098546:Interleukin-21
chemical_list: D020381:Interleukin-17; D007378:Interleukins; D053633:Receptor, Interferon alpha-beta; D018664:Interleukin-12; D007371:Interferon-gamma; D000098546:Interleukin-21
references.citation: J Immunol. 2008 Jun 1;180(11):7097-101
references.pmid: 18490706
references.citation: J Exp Med. 2004 Aug 16;200(4):527-33
references.pmid: 15302899
references.citation: Science. 2009 Jun 19;324(5934):1572-6
references.pmid: 19443735
references.citation: Curr Opin Immunol. 2000 Aug;12(4):425-31
references.pmid: 10899025
references.citation: Science. 2002 Nov 22;298(5598):1630-4
references.pmid: 12446913
references.citation: J Immunol. 2007 Apr 1;178(7):4498-505
references.pmid: 17372008
references.citation: Infect Immun. 1991 Sep;59(9):2892-900
references.pmid: 1679040
references.citation: J Immunol. 2007 Apr 1;178(7):4411-6
references.pmid: 17371998
references.citation: J Exp Med. 2004 Aug 16;200(4):535-40
references.pmid: 15302900
references.citation: Arthritis Rheum. 2007 Apr;56(4):1152-63
references.pmid: 17393408
references.citation: Microbes Infect. 2007 Aug;9(10):1208-15
references.pmid: 17719259
references.citation: J Immunol. 2008 Mar 15;180(6):4109-15
references.pmid: 18322221
references.citation: Eur J Immunol. 2008 Jul;38(7):1833-8
references.pmid: 18546146
references.citation: Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):377-81
references.pmid: 7831294
references.citation: Immunity. 2002 Apr;16(4):559-69
references.pmid: 11970879
references.citation: J Immunol. 2007 Mar 15;178(6):3822-30
references.pmid: 17339481
references.citation: J Immunol. 2007 Aug 15;179(4):2115-25
references.pmid: 17675470
references.citation: J Immunol. 2005 Apr 15;174(8):4465-9
references.pmid: 15814665
references.citation: J Leukoc Biol. 2008 Aug;84(2):348-56
references.pmid: 18467657
references.citation: J Immunol. 2002 Feb 15;168(4):1528-32
references.pmid: 11823476
references.citation: Nat Immunol. 2007 Sep;8(9):967-74
references.pmid: 17581537
references.citation: Science. 2009 Jun 19;324(5934):1569-72
references.pmid: 19423777
references.citation: Science. 2009 Jun 19;324(5934):1576-80
references.pmid: 19478140
references.citation: J Immunol. 2007 Jun 15;178(12):7640-8
references.pmid: 17548600
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1518-23
references.pmid: 19164519
references.citation: J Exp Med. 2004 Aug 16;200(4):437-45
references.pmid: 15302901
references.citation: J Endotoxin Res. 2006;12(4):246-50
references.pmid: 16953977
references.citation: J Immunol. 2005 May 15;174(10):5936-40
references.pmid: 15879085
references.citation: Nature. 2000 Nov 2;408(6808):57-63
references.pmid: 11081504
references.citation: Int Immunol. 2009 May;21(5):489-98
references.pmid: 19261692
references.citation: Nature. 2007 Jul 26;448(7152):484-487
references.pmid: 17581588
references.citation: J Immunol. 2000 Dec 15;165(12):6833-9
references.pmid: 11120806
references.citation: J Immunol. 1997 Jun 1;158(11):5297-304
references.pmid: 9164949
references.citation: Nat Rev Immunol. 2004 Oct;4(10):812-23
references.pmid: 15459672
references.citation: J Immunol. 2007 Aug 15;179(4):2074-81
references.pmid: 17675465
references.citation: J Immunol. 2008 May 15;180(10):6544-52
references.pmid: 18453573
references.citation: Cytokine Growth Factor Rev. 2007 Jun-Aug;18(3-4):223-32
references.pmid: 17509926
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3384-9
references.pmid: 17360655
references.citation: J Exp Med. 2005 Jan 3;201(1):139-48
references.pmid: 15630141
references.citation: Immunity. 1995 Jul;3(1):109-17
references.pmid: 7621071
references.citation: J Exp Med. 2003 Nov 17;198(10):1583-93
references.pmid: 14623912
references.citation: Nature. 2007 Jul 26;448(7152):480-3
references.pmid: 17581589
references.citation: J Immunol. 2004 Feb 15;172(4):2048-58
references.pmid: 14764669
references.citation: J Exp Med. 2005 Apr 4;201(7):1053-9
references.pmid: 15809350