Inefficient lymph node sensitization during respiratory viral infection promotes IL-17-mediated lung pathology

J Immunol. 2010 Oct 1;185(7):4137-47. doi: 10.4049/jimmunol.1000677. Epub 2010 Aug 30.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Separation
  • Chemotaxis, Leukocyte / immunology*
  • Choristoma / immunology
  • Choristoma / metabolism
  • Flow Cytometry
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / immunology*
  • Lung Diseases / immunology
  • Lung Diseases / virology
  • Lymph Nodes*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucus / metabolism
  • Receptors, CCR7 / deficiency
  • Receptors, CCR7 / genetics
  • Receptors, CCR7 / immunology
  • Respiratory Syncytial Virus Infections / immunology*
  • Respiratory Syncytial Virus Infections / pathology*
  • Respiratory Syncytial Viruses
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Ccr7 protein, mouse
  • Interleukin-17
  • Receptors, CCR7