Smyth M J, Sutton V R, Kershaw M H, Trapani J A
Cellular Cytotoxicity Laboratory, The Austin Research Institute, Heidelberg, Victoria, Australia.
Transplantation. 1996 Nov 27;62(10):1529-32. doi: 10.1097/00007890-199611270-00030.
Lymphocyte-mediated cytotoxicity represents one defense mechanism that contributes to transplant rejection. Comparatively little is known about the molecular mechanisms responsible for cell-mediated rejection of xenografts. Herein, we have investigated the relative contribution of perforin- and Fas- pathways in lymphocyte-mediated cytotoxicity generated in response to a variety of human cell lines and peripheral blood mononuclear cells transplanted into mice. Responder lymphocytes generated in immunocompetent mice displayed significant lysis of human targets, suggesting that normally mice can generate a strong lymphocytotoxic response to human cells. Effector cells from mice immunized with one human cell line were also cytotoxic to other human cells, indicating a cross-reactive mouse antihuman response. Effector cells generated in gld mice that have a mutated Fas ligand displayed apparently normal levels of cytotoxicity against human target cells, suggesting a predominantly perforin-based cytotoxic mechanism. This was confirmed by the low cytotoxic activity of xenospecific lymphocytes from perforin-deficient mice. The residual cytotoxicity in perforin-deficient mice responding to xenografted human cells was completely inhibited by anti-Fas mAb, suggesting that a Fas-mediated pathway can be stimulated in the absence of perforin. The detection of Fas-mediated cytotoxicity correlated with the sensitivity of human target cells to Fas-mediated lysis. Depletion of effector CD8+ T, but not CD4+ T or NK1.1+, cells almost completely inhibited lysis of human target cells, suggesting that CD8+ T cells were responsible for perforin-mediated xenospecific cytotoxicity. Overall, these data suggested that xenospecific cytotoxic T lymphocytes can lyse target cells via either perforin- or Fas-mediated pathways.
淋巴细胞介导的细胞毒性是导致移植排斥反应的一种防御机制。关于异种移植细胞介导排斥反应的分子机制，人们所知相对较少。在此，我们研究了穿孔素途径和Fas途径在针对多种移植到小鼠体内的人类细胞系和外周血单个核细胞所产生的淋巴细胞介导的细胞毒性中的相对作用。免疫活性小鼠产生的反应性淋巴细胞对人类靶细胞表现出显著的裂解作用，这表明正常情况下小鼠能够对人类细胞产生强烈的淋巴细胞毒性反应。用一种人类细胞系免疫的小鼠产生的效应细胞对其他人类细胞也具有细胞毒性，这表明存在交叉反应性的小鼠抗人类反应。在Fas配体发生突变的gld小鼠中产生的效应细胞对人类靶细胞的细胞毒性水平明显正常，这表明主要存在基于穿孔素的细胞毒性机制。穿孔素缺陷小鼠的异种特异性淋巴细胞的低细胞毒性活性证实了这一点。抗Fas单克隆抗体完全抑制了穿孔素缺陷小鼠对异种移植人类细胞产生的残余细胞毒性，这表明在没有穿孔素的情况下，Fas介导的途径可以被激活。Fas介导的细胞毒性的检测与人类靶细胞对Fas介导裂解的敏感性相关。效应性CD8⁺T细胞而非CD4⁺T细胞或NK1.1⁺细胞的耗竭几乎完全抑制了人类靶细胞的裂解，这表明CD8⁺T细胞负责穿孔素介导的异种特异性细胞毒性。总体而言，这些数据表明异种特异性细胞毒性T淋巴细胞可以通过穿孔素或Fas介导的途径裂解靶细胞。
