Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 8, Pages 2987-2992Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1217580110
Keywords
chemokines; lung infection; bronchiolitis
Categories
Funding
- Centre of Respiratory Infections
- Medical Research Council (MRC)
- Asthma UK Centre in Allergic Mechanisms of Asthma, Wellcome Trust Programme [087805/Z/08/Z]
- MRC [G0800311]
- MRC [G0800311] Funding Source: UKRI
- Asthma UK [S06/001] Funding Source: researchfish
- Medical Research Council [G1000758, G0800311] Funding Source: researchfish
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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.
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