Poster Abstracts

Abstract

Severe respiratory viral infections during infancy are a major risk factor for asthma. Whether this association is causal or the virus merely unmasks the susceptible host remains unclear. Here we used transgenic BDCA2-DTR mice to address whether conditional depletion of plasmacytoid dendritic cells (pDC) during primary Pneumovirus (pneumonia virus of mice) infection alone predisposes toward bronchiolitis in early life (2 weeks of age), and an asthma-like pathology upon reinfection in adulthood (8 weeks of age). Temporary depletion of pDC with diphtheria toxin (3 ng/g body weight/i.p. route) reduced the production of interferon alpha and lambda, increased viral load in the airway epithelium and promoted the development of severe bronchiolitis (stunted growth, airway epithelial cell sloughing, neutrophilia) and type 2 inflammation during primary virus infection. Heightened inflammation was associated with lower numbers of neuropilin- 1+ natural regulatory T cells (nTreg) and lower IL-10 and TGF-β production in the lung. The neuropilin-1 ligand semaphorin- 4a was highly expressed on pDC relative to other antigen-presenting cells and was necessary for pDC-mediated expansion of the nTreg. Viral challenge induced the hallmark features of asthma, including airways hyperreactivity, eosinophilia and type 2 inflammation but only in mice that had developed severe bronchiolitis in infancy (BDCA2- DTR+). Adoptive transfer of naïve nTreg to pDC-depleted mice during primary infection prevented both severe bronchiolitis and post-viral asthma. These data are the first to demonstrate that pDCmediated support of nTreg is necessary to limit severe virus-induced bronchiolitis and is sufficient to halt the onset of virus-provoked asthma.