Donor Fas Is Not Necessary for T‐Cell‐Mediated Rejection of Mouse Kidney Allografts

It is important to resolve whether T‐cell‐mediated rejection (TCMR) is mediated by contact‐dependent cytotoxicity or by contact‐independent inflammatory mechanisms. We recently showed that the cytotoxic molecules perforin and granzymes A and B are not required for TCMR of mouse kidney transplants. Nevertheless, TCMR could still be mediated by cytotoxicity via Fas on donor cells engaging Fas ligand on host T cells. We examined whether the diagnostic TCMR lesions would be abrogated if donor Fas was absent, particularly in hosts deficient in perforin or granzymes A and B. Kidneys from Fas‐deficient donors transplanted into major histocompatibility complex (MHC)‐ mismatched hosts developed tubulitis and diffuse interstitial infiltration indistinguishable from wild‐type (WT) allografts, even in hosts deficient in perforin and granzymes A and B. Gene expression analysis revealed similar molecular disturbances in Fas‐deficient and WT allografts at day 21 transplanted into WT, perforin and granzyme A/B‐deficient hosts, indicating epithelial injury and dedifferentiation. Thus, donor Fas is not necessary for TCMR diagnostic lesions or molecular changes, even in the absence of perforin–granzyme mechanisms. We propose that in TCMR, interstitial effector T cells mediate parenchymal injury by inflammatory mechanisms that require neither the perforin–granzyme nor the Fas–Fas ligand cytotoxic mechanisms.