Both perforin and Fas ligand are required for the regulation of alloreactive CD8+ T cells during acute graft-versus-host disease
Both perforin and Fas ligand are required for the regulation of alloreactive CD8+ T cells during acute graft-versus-host disease
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DOI：
10.1182/blood-2004-08-3036
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发表时间：
2005-03-01
期刊：
影响因子：
20.3
通讯作者：
Ferrara, JLM
中科院分区：
文献类型：
--
作者：
Maeda, Y;Levy, RB;Ferrara, JLM
Fas配体（FasL）和穿孔素通路不仅是T细胞介导的细胞毒性的主要机制，而且还参与这些T细胞的稳态调节。在本研究中，我们测试了是否CD 8（+）供体T细胞，在穿孔素和FasL（细胞毒性双缺陷[cdd]）缺陷可以诱导移植物抗宿主病（GVHD）在主要组织相容性复合物I类不匹配致死照射小鼠模型。有趣的是，在异基因骨髓移植后30天，cdd CD 8（+）T细胞的受体表现出比野生型（wt）T细胞显著更高的血清干扰素γ和肿瘤坏死因子α水平以及由GVHD引起的组织病理学损伤（P <0.05）。Wt和穿孔素缺陷或FasL缺陷的CD 8（+）T细胞在移植后早期扩增，随后是一个收缩期，其中大部分扩增的CD 8（+）T细胞被消除。相反，cdd CD 8（+）T细胞在体内和体外对同种异体抗原刺激表现出延长的扩增和减少的凋亡。这些结果共同表明，供体cdd CD 8（+）T细胞持续扩增并引起致死性GVHD，并且穿孔素和Fast-都是同种异体反应性CD 8（+）T细胞收缩所必需的。(C)2005年美国血液学会。
Fas ligand (FasL) and perforin pathways not only are the major mechanisms of T cell-mediated cytotoxicity but also are involved in homeostatic regulation of these T cells. In the present study, we tested whether CD8(+) donor T cells that are deficient in both perforin and FasL (cytotoxic double deficient [cdd]) could induce graft-versus-host disease (GVHD) in a major histocompatibility complex class I-mismatched lethally irradiated murine model. Interestingly, recipients of cdd CD8(+) T cells demonstrated significantly greater serum levels of interferon gamma and tumor necrosis factor alpha and histopathologic damage from GVHD than wild-type (wt) T cells on day 30 after allogeneic bone marrow transplantation (P < .05). Wt and either perforin-deficient or FasL-deficient CD8(+) T cells expanded early after transplantation followed by a contraction phase in which the majority of expanded CD8(+) T cells were eliminated. In contrast, cdd CD8(+) T cells exhibited prolonged expansion and reduced apoptosis to alloantigen stimulation in vivo and in vitro. Together these results suggest that donor cdd CD8(+) T cells expand continuously and cause lethal GVHD, and that both perforin and Fast-are required for the contraction of alloreactive CD8(+) T cells. (C) 2005 by The American Society of Hematology.