Inefficient lymph node sensitization during respiratory viral infection promotes IL-17-mediated lung pathology.
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.
Kallal
Lara E
LE
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Hartigan
Adam J
AJ
Hogaboam
Cory M
CM
Schaller
Matthew A
MA
Lukacs
Nicholas W
NW
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
C515371:Ccr7 protein, mouse; D020381:Interleukin-17; D054400:Receptors, CCR7
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