Sleater M, Diamond A S, Gill R G
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Department of Medicine, USA.
Am J Transplant. 2007 Aug;7(8):1927-33. doi: 10.1111/j.1600-6143.2007.01889.x.
Though CD8(+) T lymphocytes are important cellular mediators of islet allograft rejection, their molecular mechanism of rejection remains unidentified. Surprisingly, while it is generally assumed that CD8(+) T cells require classic cytotoxic mechanisms to kill grafts in vivo, neither perforin nor FasL (CD95L) are required for acute islet allograft rejection. Thus, it is unclear whether such contact-dependent cytotoxic pathways play an essential role in islet rejection. Moreover, both perforin and CD95L have been implicated in playing roles in peripheral tolerance, further obscuring the role of these effector pathways in rejection. Therefore, we determined whether perforin and/or FasL (CD95L) were required by donor MHC-restricted ('direct') CD8(+) T cells to reject islet allografts in vivo. Islet allograft rejection by primed, alloreactive CD8(+) T cells was examined independently of other lymphocyte subpopulations via adoptive transfer studies. Individual disruption of T-cell-derived perforin or allograft Fas expression had limited impact on graft rejection. However, simultaneous disruption of both pathways prevented allograft rejection in most recipients despite the chronic persistence of transferred T cells at the graft site. Thus, while there are clearly multiple cellular pathways of allograft rejection, perforin and FasL comprise alternate and necessary routes of acute CD8(+) T-cell-mediated islet allograft rejection.
虽然CD8(+) T淋巴细胞是胰岛同种异体移植排斥反应重要的细胞介质，但其排斥反应的分子机制仍不清楚。令人惊讶的是，尽管通常认为CD8(+) T细胞在体内需要经典的细胞毒性机制来杀伤移植物，但急性胰岛同种异体移植排斥反应并不需要穿孔素和FasL（CD95L）。因此，尚不清楚这种接触依赖性细胞毒性途径在胰岛排斥反应中是否起关键作用。此外，穿孔素和CD95L均与外周耐受有关，这进一步模糊了这些效应途径在排斥反应中的作用。因此，我们确定供体MHC限制性（“直接”）CD8(+) T细胞在体内排斥胰岛同种异体移植是否需要穿孔素和/或FasL（CD95L）。通过过继转移研究，独立于其他淋巴细胞亚群，检测致敏的、同种异体反应性CD8(+) T细胞引起的胰岛同种异体移植排斥反应。T细胞来源的穿孔素或移植物Fas表达的单独破坏对移植物排斥反应的影响有限。然而，尽管移植的T细胞在移植物部位长期存在，但两种途径的同时破坏在大多数受者中可防止移植物排斥反应。因此，虽然同种异体移植排斥反应显然有多种细胞途径，但穿孔素和FasL是急性CD8(+) T细胞介导的胰岛同种异体移植排斥反应的替代且必要途径。
