Fas is expressed early in human thymocyte development but does not transmit an apoptotic signal.
Fas is expressed early in human thymocyte development but does not transmit an apoptotic signal.
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DOI：
10.4049/jimmunol.163.3.1195
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发表时间：
1999-08
影响因子：
4.4
通讯作者：
M. Jenkins;M. Keir;J. McCune
中科院分区：
文献类型：
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作者：
M. Jenkins;M. Keir;J. McCune
我们研究了人胸腺细胞Fas在胎儿和儿童组织标本以及SCID-Hu Thy/Liv移植物上的表达和功能。与小鼠胸腺细胞不同，人胸腺细胞Fas表达偏向于未成熟细胞，在双阴性胸腺细胞和胸腺内T祖细胞上表达最高。Fas在双阳性胸腺细胞上呈中等表达，在成熟单阳性胸腺细胞上呈弱阳性或阴性表达。尽管Fas的表面表达相对丰富，但Fas与激动剂mAb的交联不能在人胸腺细胞中触发凋亡信号。用放线菌酮治疗不能增强细胞凋亡信号，也不能通过增加胸腺基质细胞来恢复共信号环境。小鼠胸腺细胞在体外和体内均能被交联型重组人Fas配体诱导凋亡，尽管人胸腺细胞对这种受体连接方式也具有抵抗力。膜结合的Fas配体也可诱导小鼠胸腺细胞的凋亡性死亡，但不能诱导人胸腺细胞的凋亡。然而，人类胸腺细胞与Jurkat细胞一样对肿瘤坏死因子-α诱导的细胞凋亡敏感，这表明这些细胞在激活最早的caspase之前存在信号缺陷。这些数据表明，人类胸腺细胞对Fas受体参与诱导的凋亡具有持久和特异的抵抗力，并揭示了胸腺细胞程序性细胞死亡的生物学特性的显著差异。
We investigated the expression and function of Fas on human thymocytes prepared from fetal and pediatric tissue specimens and from SCID-hu Thy/Liv grafts. Unlike mouse thymocytes, human thymocytes exhibited a pattern of Fas expression skewed to immature cells, in that the highest expression was seen on double negative thymocytes and on intrathymic T progenitor cells. Fas expression was intermediate on double positive human thymocytes, and low or negative on mature single positive CD4 and CD8 medullary thymocytes. In spite of this relatively abundant surface expression, cross-linking of Fas with agonist mAb was incapable of triggering an apoptotic signal in human thymocytes. Apoptotic signaling was not enhanced by treatment with cycloheximide, nor by restoring a cosignaling milieu by addition of thymic stromal cells. Mouse thymocytes were induced to apoptosis by cross-linked recombinant soluble human Fas ligand both in vitro and in vivo, though human thymocytes were also resistant to this mode of receptor ligation. Membrane-bound Fas ligand also induced apoptotic death in murine thymocytes but not in human thymocytes. Human thymocytes were as sensitive as Jurkat cells, however, to apoptosis induced by TNF-alpha, suggesting that these cells have a signaling defect before activation of the earliest caspases. These data demonstrate a durable and specific resistance of human thymocytes to apoptosis induced through Fas receptor engagement, and reveal significant species-specific differences in the biology of thymocyte-programmed cell death.