title: Inefficient lymph node sensitization during respiratory viral infection promotes IL-17-mediated lung pathology.
abstract: Development of bronchus-associated lymphoid tissue has been suggested to enhance local antiviral immune responses; however, ectopic lymph node formation often corresponds to chronic inflammatory diseases. These studies investigated the role of ectopic pulmonary lymph nodes upon respiratory syncytial virus (RSV) infection using CCR7-deficient mice, which develop bronchus-associated lymphoid tissue early in life. CCR7(-/-) mice exhibited impaired secondary lymph node formation, enhanced effector T cell responses and pathogenic mucus production in the lung after RSV infection. IL-17 production from CD4 T cells in CCR7(-/-) mice was most remarkably enhanced. Wild-type animals reconstituted with CCR7(-/-) bone marrow recapitulated the pathogenic lung phenotype in CCR7(-/-) mice, whereas CCR7(-/-) animals reconstituted with wild-type bone marrow had normal lymph node development, diminished IL-17 production and reduced lung pathology. Mixed bone marrow chimeras revealed an alteration of immune responses only in CCR7(-/-) T cells, suggesting that impaired trafficking promotes local effector cell generation. Lymphotoxin-α-deficient mice infected with RSV were used to further examine locally induced immune responses and demonstrated increased mucus production and amplified cytokine responses in the lung, especially IL-17. Neutralization of IL-17 in CCR7(-/-) or in lymphotoxin-α-deficient animals specifically inhibited mucus hypersecretion and reduced IL-13. Thus, immune cell trafficking to secondary lymph nodes is necessary for appropriate cytokine responses to RSV as well as modulation of the local environment.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lara E
authors.initials: LE
authors.lastname: Kallal
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Hartigan
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schaller
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
mesh_terms: D000818:Animals; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D002828:Choristoma / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D008171:Lung Diseases / Q000276:immunology / Q000821:virology; D008198:Lymph Nodes; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism; D054400:Receptors, CCR7 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology*; D012136:Respiratory Syncytial Viruses; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: C515371:Ccr7 protein, mouse; D020381:Interleukin-17; D054400:Receptors, CCR7
references.citation: J Immunol. 2008 Nov 15;181(10):6984-94
references.pmid: 18981118
references.citation: J Virol. 2009 May;83(9):4185-94
references.pmid: 19211758
references.citation: Vaccine. 1999 Jan;17(2):172-81
references.pmid: 9987152
references.citation: Eur J Immunol. 1998 Sep;28(9):2760-9
references.pmid: 9754563
references.citation: Am J Pathol. 2001 Sep;159(3):861-73
references.pmid: 11549579
references.citation: J Exp Med. 2009 Nov 23;206(12):2593-601
references.pmid: 19917776
references.citation: J Immunol. 2004 Dec 1;173(11):6684-93
references.pmid: 15557160
references.citation: Nat Rev Immunol. 2006 Mar;6(3):205-17
references.pmid: 16498451
references.citation: J Biol Chem. 2003 May 9;278(19):17036-43
references.pmid: 12624114
references.citation: Eur Respir J. 2009 Jul;34(1):219-30
references.pmid: 19567605
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12694-9
references.pmid: 11070085
references.citation: Nat Med. 2004 Sep;10(9):927-34
references.pmid: 15311275
references.citation: Am J Respir Crit Care Med. 2009 Oct 15;180(8):720-30
references.pmid: 19661246
references.citation: J Immunol. 2002 Nov 1;169(9):5236-43
references.pmid: 12391242
references.citation: J Allergy Clin Immunol. 2009 Oct;124(4):761-70.e1
references.pmid: 19815118
references.citation: J Allergy Clin Immunol. 2007 May;119(5):1086-91
references.pmid: 17313976
references.citation: Nature. 2009 Mar 19;458(7236):351-6
references.pmid: 19182775
references.citation: J Immunol. 2009 Nov 15;183(10):6236-43
references.pmid: 19841186
references.citation: Semin Immunol. 2008 Feb;20(1):26-42
references.pmid: 18243731
references.citation: J Immunol. 2006 Feb 1;176(3):1937-42
references.pmid: 16424225
references.citation: Cell. 1999 Oct 1;99(1):23-33
references.pmid: 10520991
references.citation: J Immunol. 2009 Oct 15;183(8):5301-10
references.pmid: 19783685
references.citation: Science. 2009 Nov 13;326(5955):986-91
references.pmid: 19797626
references.citation: Arthritis Rheum. 2003 Nov;48(11):3187-201
references.pmid: 14613282
references.citation: J Infect Dis. 2006 Feb 1;193(3):438-41
references.pmid: 16388492
references.citation: J Exp Med. 2005 May 2;201(9):1447-57
references.pmid: 15851484
references.citation: J Immunol. 1992 Dec 15;149(12):3881-8
references.pmid: 1281193
references.citation: J Exp Med. 2007 Apr 16;204(4):723-34
references.pmid: 17371929
references.citation: J Immunol. 2007 Jun 1;178(11):6725-9
references.pmid: 17513718
references.citation: Nat Rev Immunol. 2003 Apr;3(4):292-303
references.pmid: 12669020
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4793-8
references.pmid: 19273860
references.citation: Pediatr Infect Dis J. 2008 Oct;27(10 Suppl):S63-70
references.pmid: 18820581
references.citation: J Immunol. 2001 Mar 1;166(5):3542-8
references.pmid: 11207314
references.citation: J Immunol. 2001 Jul 15;167(2):1060-5
references.pmid: 11441116
references.citation: J Clin Invest. 2005 Feb;115(2):313-25
references.pmid: 15668741
references.citation: J Allergy Clin Immunol. 2004 Jan;113(1 Suppl):S15-8
references.pmid: 14694345
references.citation: Am J Respir Crit Care Med. 2004 Aug 1;170(3):306-12
references.pmid: 15130904
references.citation: Clin Exp Immunol. 2009 Aug;157(2):316-24
references.pmid: 19604272
references.citation: J Virol. 2009 Apr;83(7):3019-28
references.pmid: 19153229
references.citation: Am J Pathol. 2006 Sep;169(3):977-86
references.pmid: 16936271
references.citation: J Pathol. 2001 Feb;193(2):263-9
references.pmid: 11180175
references.citation: J Immunol. 2009 Jun 1;182(11):6861-9
references.pmid: 19454682
references.citation: Arthritis Rheum. 1984 Jan;27(1):32-9
references.pmid: 6197977
references.citation: J Pediatr. 2003 Nov;143(5 Suppl):S112-7
references.pmid: 14615709
references.citation: Lymphology. 2001 Mar;34(1):22-9
references.pmid: 11307662