ABSTRACTFMS-like tyrosine kinase-3 ligand (Flt3L) is a dendritic cell (DC) growth and differentiation factor with potential in antitumor therapies and antibacterial immunization strategies. However, the effect of systemic Flt3L treatment on lung-protective immunity against bacterial infection is incompletely defined. Here, we examined the impact of deficient (in Flt3L knockout [KO] mice), normal (in wild-type [WT] mice), or increased Flt3L availability (in WT mice pretreated with Flt3L for 3, 5, or 7 days) on lung DC subset profiles and lung-protective immunity against the major lung-tropic pathogen,Streptococcus pneumoniae. Although in Flt3L-deficient mice the numbers of DCs positive for CD11b (CD11bposDCs) and for CD103 (CD103posDCs) were diminished, lung permeability, a marker of injury, was unaltered in response toS. pneumoniae. In contrast, WT mice pretreated with Flt3L particularly responded with increased numbers of CD11bposDCs and with less pronounced numbers of CD103posDCs and impaired bacterial clearance and with increased lung permeability followingS. pneumoniae challenge. Notably, infection of Flt3L-pretreated mice withS. pneumoniaelacking the pore-forming toxin, pneumolysin (PLY), resulted in substantially less lung CD11bposDCs activation and reduced lung permeability. Collectively, this study establishes that Flt3L treatment enhances the accumulation of proinflammatory activated lung CD11bposDCs which contribute to acute lung injury in response to PLY released byS. pneumoniae.
Tumor Suppressor CYLD Regulates Acute Lung Injury in Lethal Streptococcus pneumoniae Infections
