Defective immunoregulation in RSV vaccine-augmented viral lung disease restored by selective chemoattraction of regulatory T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 8; pp. 2987 - 2992
• Main Authors: Loebbermann, Jens, Durant, Lydia, Thornton, Hannah, Johansson, Cecilia, Openshaw, Peter J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.02.2013; National Acad Sciences
• Subjects: Adoptive Transfer; Aldehydes; Animals; Autoimmune diseases; Babies; Biological Sciences; Bronchoalveolar Lavage Fluid; Chemokines; Chemokines - metabolism; Diabetes; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Human respiratory syncytial virus; Infections; Lung diseases; Lungs; Mice; Mice, Inbred BALB C; Real-Time Polymerase Chain Reaction; Respiratory syncytial virus infections; Respiratory Syncytial Virus Infections - immunology; Respiratory Syncytial Viruses - immunology; Rodents; T cell receptors; T lymphocytes; T-Lymphocytes, Regulatory - immunology; Tissues; Vaccination; Vaccines; Viral Vaccines - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1217580110

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.