IL-4-Secreting NKT Cells Prevent Hypersensitivity Pneumonitis by Suppressing IFN-γ-Producing Neutrophils

Hypersensitivity pneumonitis (HP) is mediated by Th1 immune response. NKT cells regulate immune responses by modulating the Th1/Th2 balance. Therefore, we postulated that NKT cells play a critical role in the development of the HP by modulating the Th1/Th2 response. To address this issue, we explored the functional roles of NKT cells in Saccharopolyspora rectivirgula (SR)-induced HP. In CD1d−/− mice, the HP was worse in terms of histological changes, hydroxyproline levels, the CD4:CD8 ratio in bronchoalveolar lavage fluid, and SR-specific immune responses than in control mice. CD1d−/− mice showed elevated IFN-γ production in the lung during the HP, and this was produced mainly by Gr-1+ neutrophils. The blockade of IFN-γ in CD1d−/− mice attenuated the HP, whereas the injection of rIFN-γ aggravated it. Moreover, the depletion of Gr-1+ neutrophils reduced CD8+ T cell numbers in bronchoalveolar lavage fluid during the HP. The adoptive transfer of IL-4−/− mouse NKT cells did not attenuate the HP, whereas wild-type or IFN-γ−/− mouse NKT cells suppressed the HP. In conclusion, NKT cells producing IL-4 play a protective role in SR-induced HP by suppressing IFN-γ-producing neutrophils, which induce the activation and proliferation of CD8+ T cells in the lung.