Impaired gamma delta T cell-derived IL-17A and inflammasome activation during early respiratory syncytial virus infection in infants

Immunol Cell Biol. 2015 Feb;93(2):126-35. doi: 10.1038/icb.2014.79. Epub 2014 Sep 30.

Abstract

Respiratory syncytial virus (RSV) infection remains a significant global health burden disproportionately affecting infants and leading to long-term lung disease. Interleukin (IL)-17A has been shown to be involved in regulating viral and allergic lung inflammatory responses, which has led to a more recent interest in its role in RSV infection. Using a neonatal mouse model of RSV, we demonstrate that neonates fail to develop IL-17A responses compared with adult mice; the main immediate IL-17A contributor in adults were γδ T cells. Antibody neutralization of IL-17A in adult mice caused increased lung inflammation and airway mucus from RSV, whereas exogenous IL-17A administration to RSV-infected neonates caused decreased inflammation but no change in airway mucus. We also observed a lack of pro-inflammatory cytokine production (IL-1β, IL-6) from infected neonates. Using human cord blood mononuclear cells (CBMCs) and adult peripheral blood mononuclear cells (PBMCs), we compared inflammasome activation by direct retinoic acid-inducible gene I agonism; CBMCs failed to induce pro-inflammatory cytokines or IL-17A(+) γδ T cells compared with PBMCs. Our results indicate that RSV disease severity is in part mediated by a lack of inflammasome activation and IL-17A production in neonates.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Adult
  • Animals
  • Animals, Newborn
  • Disease Models, Animal
  • Fetal Blood / cytology
  • Humans
  • Infant, Newborn
  • Inflammasomes / metabolism*
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism*
  • Mice, Inbred BALB C
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Respiratory Syncytial Virus Infections / immunology*
  • Respiratory Syncytial Virus Infections / pathology
  • Respiratory Syncytial Virus Infections / virology*
  • Respiratory Syncytial Viruses / immunology*
  • T-Lymphocytes / immunology

Substances

  • Inflammasomes
  • Interleukin-17
  • Receptors, Antigen, T-Cell, gamma-delta
  • Interferon-gamma