Exocytosis of CTLA-4 is dependent on phospholipase D and ADP ribosylation factor-1 and stimulated during activation of regulatory T cells
Exocytosis of CTLA-4 is dependent on phospholipase D and ADP ribosylation factor-1 and stimulated during activation of regulatory T cells
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DOI：
10.4049/jimmunol.174.8.4803
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发表时间：
2005-04-15
影响因子：
4.4
通讯作者：
Sansom, DM
中科院分区：
文献类型：
--
作者：
Mead, KI;Zheng, Y;Sansom, DM
CTLA-4是调节T细胞应答的必需蛋白，其与APC表面上发现的两种配体（CD 80和CD 86）相互作用。CTLA-4本身在T细胞表面上表达较差，并且主要定位于细胞内区室。我们已经研究了CTLA-4的传递到细胞表面的机制，使用模型中国仓鼠卵巢细胞系统，并与激活和调节的人T细胞进行比较。我们已经表明，在质膜（PM）上的CTLA-4的表达是由含有CTLA-4的囊泡的胞吐作用和随后的快速内吞作用控制的。使用选择性抑制剂和显性阴性突变体，我们已经表明，CTLA-4的胞吐作用依赖于GTP酶ADP核糖基化因子-1的活性和磷脂酶D的活性。CTLA-4在与顺式高尔基体标记物GM-130重叠的核周区室中被鉴定，但与溶酶体标记物如CD 63和溶酶体相关膜蛋白没有强烈的共定位。在调节性T细胞中，磷脂酶D的激活足以触发CTLA-4释放到PM，但不抑制内吞作用。总之，这些数据表明，CTLA-4可以储存在一个专门的隔室中的调节性T细胞，可以迅速触发部署到PM的磷脂酶D和ADP核糖基化因子-1依赖性的方式。
CTLA-4 is an essential protein in the regulation of T cell responses that interacts with two ligands found on the surface of APCs (CD80 and CD86). CTLA-4 is itself poorly expressed on the T cell surface and is predominantly localized to intracellular compartments. We have studied the mechanisms involved in the delivery of CTLA-4 to the cell surface using a model Chinese hamster ovary cell system and compared this with activated and regulatory human T cells. We have shown that expression of CTLA-4 at the plasma membrane (PM) is controlled by exocytosis of CTLA-4-containing vesicles and followed by rapid endocytosis. Using selective inhibitors and dominant negative mutants, we have shown that exocytosis of CTLA-4 is dependent on the activity of the GTPase ADP ribosylation factor-1 and on phospholipase D activity. CTLA-4 was identified in a perinuclear compartment overlapping with the cis-Golgi marker GM-130 but did not colocalize strongly with lysosomal markers such as CD63 and lysosome-associated membrane protein. In regulatory T cells, activation of phospholipase D was sufficient to trigger release of CTLA-4 to the PM but did not inhibit endocytosis. Taken together, these data suggest that CTLA-4 may be stored in a specialized compartment in regulatory T cells that can be triggered rapidly for deployment to the PM in a phospholipase D- and ADP ribosylation factor-1-dependent manner.