Cytotoxicity of Natural Killer Cells Activated Through NKG2D Contributes to the Development of Bronchiolitis Obliterans in a Murine Heterotopic Tracheal Transplant Model

Bronchiolitis obliterans after lung transplantation is a major cause of postoperative mortality in which T cell–mediated immunity is known to play an important role. However, the exact contribution of natural killer (NK) cells, which have functions similar to CD8⁺ T cells, has not been defined. Here, we assessed the role of NK cells in murine bronchiolitis obliterans through heterotopic tracheal transplantations and found a greater percentage of NK cells in allografts than in isografts. Depletion of NK cells using an anti‐NK1.1 antibody attenuated bronchiolitis obliterans in transplant recipients compared with controls. In terms of NK cell effector functions, an improvement in bronchiolitis obliterans was observed in perforin‐KO recipient mice compared to wild type (WT). Furthermore, we found upregulation of NKG2D‐ligand in allografts and demonstrated the significance of this using grafts expressing Rae‐1, a murine NKG2D‐ligand, which induced severe bronchiolitis obliterans in WT and Rag‐1 KO recipients. This effect was ameliorated by injection of anti‐NKG2D blocking antibody. Together, these results suggest that cytotoxicity resulting from activation of NK cells through NKG2D leads to the development of murine bronchiolitis obliterans.