title: Defective immunoregulation in RSV vaccine-augmented viral lung disease restored by selective chemoattraction of regulatory T cells.
abstract: Human trials of formaldehyde-inactivated respiratory syncytial virus (FI-RSV) vaccine in 1966-1967 caused disastrous worsening of disease and death in infants during subsequent natural respiratory syncytial virus (RSV) infection. The reasons behind vaccine-induced augmentation are only partially understood, and fear of augmentation continues to hold back vaccine development. We now show that mice vaccinated with FI-RSV show enhanced local recruitment of conventional CD4(+) T cells accompanied by a profound loss of regulatory T cells (Tregs) in the airways. This loss of Tregs was so complete that additional depletion of Tregs (in transgenic depletion of regulatory T-cell mice) produced no additional disease enhancement. Transfer of conventional CD4(+) T cells from FI-RSV-vaccinated mice into naive RSV-infected recipients also caused a reduction in airway Treg responses; boosting Tregs with IL-2 immune complexes failed to restore normal levels of Tregs or to ameliorate disease. However, delivery of chemokine ligands (CCL) 17/22 via the airway selectively recruited airway Tregs and attenuated vaccine-augmented disease, reducing weight loss and inhibiting local recruitment of pathogenic CD4(+) T cells. These findings reveal an unexpected mechanism of vaccine-induced disease augmentation and indicate that selective chemoattraction of Tregs into diseased sites may offer a novel approach to the modulation of tissue-specific inflammation.
authors: Centre for Respiratory Infection, Department of Respiratory Medicine, National Heart and Lung Institute, Faculty of Medicine,  Imperial College, London W2 1PG,  United Kingdom.
authors: Jens
authors: J
authors: Loebbermann
authors: Lydia
authors: L
authors: Durant
authors: Hannah
authors: H
authors: Thornton
authors: Cecilia
authors: C
authors: Johansson
authors: Peter J
authors: PJ
authors: Openshaw
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018925:Chemokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D060888:Real-Time Polymerase Chain Reaction; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D018925:Chemokines; D014765:Viral Vaccines
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