Interferon Gamma and Contact‐dependent Cytotoxicity Are Each Rate Limiting for Natural Killer Cell–Mediated Antibody‐dependent Chronic Rejection

Natural killer (NK) cells are key components of the innate immune system. In murine cardiac transplant models, donor‐specific antibodies (DSA), in concert with NK cells, are sufficient to inflict chronic allograft vasculopathy independently of T and B cells. In this study, we aimed to determine the effector mechanism(s) required by NK cells to trigger chronic allograft vasculopathy during antibody‐mediated rejection. Specifically, we tested the relative contribution of the proinflammatory cytokine interferon gamma (IFN‐γ) versus the contact‐dependent cytotoxic mediators of perforin and the CD95/CD95L (Fas/Fas ligand FasL]) pathway for triggering these lesions. C3H/HeJ cardiac allografts were transplanted into immune‐deficient C57BL/6 rag^?/?γc^?/? recipients, who also received monoclonal anti–major histocompatibility complex (MHC) class I DSA. The combination of DSA and wild‐type NK cell transfer triggered aggressive chronic allograft vasculopathy. However, transfer of IFN‐γ–deficient NK cells or host IFN‐γ neutralization led to amelioration of these lesions. Use of either perforin‐deficient NK cells or CD95 (Fas)–deficient donors alone did not alter development of vasculopathy, but simultaneous disruption of NK cell–derived perforin and allograft Fas expression resulted in prevention of these abnormalities. Therefore, both NK cell IFN‐γ production and contact‐dependent cytotoxic activity are rate‐limiting effector pathways that contribute to this form of antibody‐induced chronic allograft vasculopathy.