Regulation of cell surface expression of CTLA-4 by secretion of CTLA-4-containing lysosomes upon activation of CD4+ T cells
Regulation of cell surface expression of CTLA-4 by secretion of CTLA-4-containing lysosomes upon activation of CD4+ T cells
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DOI：
10.4049/jimmunol.165.9.5062
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发表时间：
2000-11-01
影响因子：
4.4
通讯作者：
Saito, T
中科院分区：
文献类型：
--
作者：
Iida, T;Ohno, H;Saito, T
CTLA-4在活化的T细胞的表面上表达并负调节T细胞活化，因为CTLA-4在细胞表面上的低水平表达足以在T细胞中诱导负信号，所以CTLA-4的表面表达受到严格调节，我们以前证明了CTLA-4与网格蛋白相关的衔接子复合物AP-2的结合诱导了CTLA-4的内化。然而，在刺激时诱导细胞表面上的高表达的机制尚未阐明。为了解决这一问题，我们通过分析CTLA-4在野生型和突变型CTLA-4转染的Th 1克隆中的定位和运输来研究CTLA-4的细胞内动力学。CTLA-4在溶酶体中在短时间内被降解，并且降解过程可能充当调节CTLA-4表达的机制之一。在TCR刺激后，分泌含有CTLA-4的溶酶体，如通过分泌组织蛋白酶D和β-己糖胺酶与CTLA-4和溶酶体糖蛋白85（溶酶体标记物）的表面表达的增加平行证明的。这些结果表明，CTLA-4的细胞表面表达上调后，刺激通过利用分泌溶酶体在CD 4（+）T细胞的机制。
CTLA-4 is expressed on the surface of activated T cells and negatively regulates T cell activation, Because a low-level expression of CTLA-4 on the cell surface is sufficient to induce negative signals in T cells, the surface expression of CTLA-4 is strictly regulated, We previously demonstrated that the association of CTLA-4 with the clathrin-associated adaptor complex AP-2 induces internalization of CTLA-4 and keeps the surface expression low, However, the mechanism to induce high expression on the cell surface upon stimulation has not yet been clarified. To address this, we investigated the intracellular dynamics of CTLA-4 by analyzing its localization and trafficking in wild-type and mutant CTLA-4-transfected Th1 clones, CTEA-4 is accumulated in intracellular granules, which we identified as lysosomes. CTLA-4 is degraded in lysosomes in a short period, and the degradation process may serve as one of the mechanisms to regulate CTLA-4 expression, Upon TCR stimulation, CTLA-4-containing lysosomes are secreted as proven by the secretion of cathepsin D and beta -hexosaminidase in parallel with the increase of surface expression of CTLA-4 and lysosomal glycoprotein 85, a lysosomal marker. These results suggest that the cell surface expression of CTLA-4 is up-regulated upon stimulation by utilizing a mechanism of secretory lysosomes in CD4(+) T cells.