Djerbi M, Malinowski M M, Yagita H, Zhivotovsky B, Grandien A
Department of Immunology, The Wenner-Gren Institute, University of Stockholm, Stockholm, Sweden.
Scand J Immunol. 2007 Oct;66(4):410-21. doi: 10.1111/j.1365-3083.2007.01957.x.
Apart from the conventional Fas signalling pathway, alternative pathways including the mitochondrial caspase-dependent and RIP-mediated cell death routes have been proposed to operate during Fas-mediated cell death. To evaluate the contribution of different Fas signalling pathways, mice overexpressing FLIP(L), Bcl-x(L), a kinase-deficient form of RIP (RIPDeltakin) or combinations thereof were generated by retroviral gene transfer of haematopoietic stem cells. Such mice did not show overt abnormalities in haematopoietic development, defects in thymic deletion, accumulation of double-negative T cells or signs of autoimmunity. Fas-mediated death of mitogen-activated T cells was caspase dependent and could be blocked by FLIP(L) overexpression only with the minor involvement of Bcl-x(L) or RIPDeltakin inhibitable pathways. Fas-mediated death of resting CD4(+) and CD8(+) T cells was mainly caspase dependent but could only partly be blocked by FLIP(L) overexpression. Both Bcl-x(L) or RIPDeltakin expression resulted in partial protection of CD8(+) T cells against Fas-mediated cell death. These results indicate that yet uncharacterized signalling pathways from the Fas receptor are critically involved in lymphoproliferative and autoimmune disease observed in lpr mice and autoimmune lymphoproliferative syndrome patients.
除了传统的Fas信号通路外，还提出了包括线粒体半胱天冬酶依赖性和RIP介导的细胞死亡途径在内的替代途径在Fas介导的细胞死亡过程中发挥作用。为了评估不同Fas信号通路的作用，通过造血干细胞的逆转录病毒基因转移产生了过表达FLIP(L)、Bcl-x(L)、RIP的激酶缺陷形式（RIPDeltakin）或其组合的小鼠。这些小鼠在造血发育方面未表现出明显异常，胸腺细胞缺失无缺陷，双阴性T细胞无积累或自身免疫迹象。丝裂原激活的T细胞的Fas介导的死亡依赖于半胱天冬酶，并且仅在Bcl-x(L)或RIPDeltakin可抑制途径的轻微参与下，可被FLIP(L)过表达阻断。静息CD4(+)和CD8(+) T细胞的Fas介导的死亡主要依赖于半胱天冬酶，但仅部分可被FLIP(L)过表达阻断。Bcl-x(L)或RIPDeltakin的表达均导致CD8(+) T细胞对Fas介导的细胞死亡有部分保护作用。这些结果表明，Fas受体的尚未明确的信号通路在lpr小鼠和自身免疫性淋巴增殖综合征患者中观察到的淋巴增殖和自身免疫性疾病中起关键作用。
