Natural Killer T (NKT) Cells Attenuate Bleomycin-Induced Pulmonary Fibrosis by Producing Interferon-γ

Pulmonary fibrosis is a progressive illness characterized by interstitial fibrosis. Although the precise mechanism for pulmonary fibrosis is not completely understood, an immune response involving interferon (IFN)-γ appears to play a role. Therefore, we examined the functional roles of natural killer T (NKT) cells, which produce IFN-γ and interleukin-4 on activation, in bleomycin-induced pulmonary fibrosis. In NKT cell-deficient mice, pulmonary fibrosis was worse in terms of histology, hydroxyproline levels, and mortality than in control mice. The transforming growth factor (TGF)-β1 levels were higher in the lung after injecting bleomycin, and blockade of TGF-β1 by neutralizing monoclonal antibody attenuated the pulmonary fibrosis in CD1d−/− mice. In contrast, the production of IFN-γ was reduced in lungs from CD1d−/− mice. Moreover, the adoptive transfer of NKT cells into CD1d−/− mice increased IFN-γ and reduced TGF-β1 production, attenuating pulmonary fibrosis. An in vitro assay demonstrated that IFN-γ was involved in suppressing TGF-β1 production in cells collected from bronchoalveolar lavage. The adoptive transfer of NKT cells from IFN-γ−/− mice did not reverse pulmonary fibrosis or TGF-β1 production in lungs of CD1d−/− mice whereas NKT cells from B6 control mice attenuated fibrosis and reduced TGF-β1 production. In conclusion, IFN-γ-producing NKT cells play a novel anti-fibrotic role in pulmonary fibrosis by regulating TGF-β1 production.