Nonlymphoid Fas ligand in peptide-induced peripheral lymphocyte deletion
Nonlymphoid Fas ligand in peptide-induced peripheral lymphocyte deletion
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DOI：
10.1073/pnas.262660999
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发表时间：
2002-12-10
影响因子：
11.1
通讯作者：
Green, DR
中科院分区：
文献类型：
--
作者：
Pinkoski, MJ;Droin, NM;Green, DR
外周淋巴细胞的缺失是减少淋巴细胞数量的必要条件。外周缺失部分是由死亡受体Fas （CD95）及其配体Fas配体（FasL; CD95L）参与细胞凋亡激活介导的，以及其他机制。本研究使用T细胞受体（TCR）转基因动物来检测诱导非淋巴样FasL表达在肽抗原应答中的作用。TCR转基因小鼠的抗原性攻击导致FasL在包括小肠上皮在内的许多非淋巴组织中的表达增加。在过继转移系统中，将TCR转基因T细胞转移到受体动物中，也获得了类似的结果。非淋巴细胞FasL在外周缺失中的功能相关性得到了以下观察结果的支持：FasL缺陷的黄金动物对转移的抗原特异性淋巴细胞的清除率显著降低，尽管这些淋巴细胞本身是FasL的野生型。这些观察结果进一步得到转基因小鼠模型的支持，其中lacZ在FasL基因近端启动子的控制下表达。使用这些转基因小鼠，我们观察到FasL启动子在整个隐窝和绒毛的肠上皮细胞中诱导活性，我们还观察到活化T细胞的浸润。这些数据表明，非淋巴样FasL的表达响应外周T细胞的激活，并参与T细胞浸润外周组织的调节。
Peripheral lymphocyte deletion is required for reduction of lymphocyte numbers after expansion in response to antigen. Peripheral deletion is mediated in part by the activation of apoptosis by engagement of the death receptor, Fas (CD95), by its ligand, Fas ligand (FasL; CD95L), among other mechanisms. Here we used T cell receptor (TCR) transgenic animals to examine the role of inducible expression of nonlymphoid FasL in response to peptide antigen. Antigenic challenge of TCR transgenic mice resulted in increased expression of FasL in a number of nonlymphoid tissues including the epithelium of the small intestine. Similar results were obtained in an adoptive transfer system in which TCR transgenic T cells were transferred into recipient animals. The functional relevance of nonlymphoid FasL in peripheral deletion is supported by the observation that FasL-deficient gld animals showed a significantly reduced rate of clearance of transferred antigen-specific lymphocytes, although the lymphocytes themselves were wild type for FasL. These observations were supported further by studies in a transgenic mouse model where lacZ was expressed under the control of the proximal promoter of the FasL gene. Using these transgenic mice, we observed induced activity of the FasL promoter in intestinal epithelial cells throughout the crypts and villi, where we also observed infiltration of activated T cells. These data demonstrate that nonlymphoid FasL is expressed in response to peripheral T cell activation and participates in the regulation of T cells that infiltrate peripheral tissues.