Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae

Interleukin ( IL)-23 is a heterodimeric cytokine that shares the identical p40 subunit as IL-12 but exhibits a unique p19 subunit similar to IL-12 p35. IL-12/23 p40, interferon gamma ( IFN-gamma), and IL-17 are critical for host defense against Klebsiella pneumoniae. In vitro, K. pneumoniae pulsed dendritic cell culture supernatants elicit T cell IL-17 production in a IL-23-dependent manner. However, the importance of IL-23 during in vivo pulmonary challenge is unknown. We show that IL-12/23 p40-deficient mice are exquisitely sensitive to intrapulmonary K. pneumoniae inoculation and that IL-23 p19(-/-), IL-17R(-/-), and IL-12 p35(-/-) mice also show increased susceptibility to infection. p40(-/-) mice fail to generate pulmonary IFN-gamma, IL-17, or IL-17F responses to infection, whereas p35(-/-) mice show normal IL-17 and IL-17F induction but reduced IFN-gamma. Lung IL-17 and IL-17F production in p19(-/-) mice was dramatically reduced, and this strain showed substantial mortality from a sublethal dose of bacteria ( 10 3 CFU), despite normal IFN-gamma induction. Administration of IL-17 restored bacterial control in p19(-/-) mice and to a lesser degree in p40(-/-) mice, suggesting an additional host defense requirement for IFN-gamma in this strain. Together, these data demonstrate independent requirements for IL-12 and IL-23 in pulmonary host defense against K. pneumoniae, the former of which is required for IFN-gamma expression and the latter of which is required for IL-17 production.