Key Role for Respiratory CD103+ Dendritic Cells, IFN-γ, and IL-17 in Protection Against Streptococcus pneumoniae Infection in Response to α-Galactosylceramide

Background. Exogenous activation of pulmonary invariant natural killer T (iNKT) cells, a population of lipid-reactive alpha beta T lymphocytes, with use of mucosal alpha-galactosylceramide (alpha-GalCer) administration, is a promising approach to control respiratory bacterial infections. We undertook the present study to characterize mechanisms leading to alpha-GalCer-mediated protection against lethal infection with Streptococcus pneumoniae serotype 1, a major respiratory pathogen in humans. Methods and Results.alpha-GalCer was administered by the intranasal route before infection with S. pneumoniae. We showed that respiratory dendritic cells (DCs), most likely the CD103(+) subset, play a major role in the activation (IFN-gamma and IL-17 release) of pulmonary iNKT cells, whereas alveolar and interstitial macrophages are minor players. After challenge, S. pneumoniae was rapidly (4 hours) eliminated in the alveolar spaces, a phenomenon that depended on respiratory DCs and neutrophils, but not macrophages, and on the early production of both IFN-gamma and IL-17. Protection was also associated with the synthesis of various interferon-dependent and IL-17-associated genes as revealed by transcriptomic analysis. Conclusions.These data imply a new function for pulmonary CD103(+) DCs in mucosal activation of iNKT cells and establish a critical role for both IFN-gamma and IL-17 signalling pathways in mediating the innate immune response to S. pneumoniae.