Cytotoxic T lymphocyte antigen 4 and CD28 modulate cell surface raft expression in their regulation of T cell function
Cytotoxic T lymphocyte antigen 4 and CD28 modulate cell surface raft expression in their regulation of T cell function
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DOI：
10.1084/jem.194.11.1675
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发表时间：
2001-12-03
影响因子：
15.3
通讯作者：
Rudd, CE
中科院分区：
文献类型：
--
作者：
Martin, M;Schneider, H;Rudd, CE
辅助受体CD 28和细胞毒性T淋巴细胞抗原（CTLA）-4对T细胞的TcR/CD 3活化具有相反的作用。虽然CD 28增强和CTLA-4抑制活化，但这些作用的潜在分子基础尚未建立。在这种情况下，富含神经节苷脂和胆固醇的膜微区（筏，GEM）作为T细胞中的信号传导中心。虽然CD 28可以促进TcR/筏共定位，但缺乏证据表明膜筏的表面表达是否可以通过CTLA-4调节T细胞应答。在这项研究中，我们证明，CD 28和CTLA-4深刻地改变膜筏的表面表达在T细胞活化。虽然CD 28增加了响应于TcR连接而诱导表达表面筏的外周T细胞的表达和数量，但CTLA-4有效地抑制了TcR和TcR x CD 28诱导的T细胞表面上的筏表达。与此一致，CD 28增加了纯化膜筏中活化T细胞（LAT）接头的存在，而CTLA-4共连接有效地阻断了这种增加。此外，用CD 3/CD 28连接逆转CTLA-4阻断伴随着表面筏表达和相关LAT的增加。我们的观察首次证明CTLA-4靶向将筏释放到T细胞表面，并为CD 28和CTLA-4对共刺激的相反作用提供了机制。
Coreceptors CD28 and cytotoxic T lymphocyte antigen (CTLA)-4 have opposing effects on TcR/CD3 activation of T cells. While CD28 enhances and CTLA-4 inhibits activation, the underlying molecular basis of these effects has yet to be established. In this context, ganglioside and cholesterol enriched membrane microdomains (rafts, GEMs) serve as centers of signaling in T cells. Although CD28 can promote TcR/raft colocalization, evidence is lacking on whether the surface expression of membrane rafts can be targeted by CTLA-4 in its modulation of T cell responses. In this study, we demonstrate that both CD28 and CTLA-4 profoundly alter the surface expression of membrane rafts during T cell activation. While CD28 increased expression and the number of peripheral T cells induced to express surface rafts in response to TcR ligation, CTLA-4 potently inhibited both TcR and TcR x CD28 induced raft expression on the surface of T cells. Consistent with this, CD28 increased the presence of the linker of activated T cells (LAT) in purified membrane rafts, while CTLA-4 coligation effectively blocked this increase. Further, the reversal of the CTLA-4 block with CD3/CD28 ligation was accompanied by an increase in surface raft expression and associated LAT. Our observations demonstrate for the first time that CTLA-4 targets the release of rafts to the surface of T cells, and provides a mechanism for the opposing effects of CD28 and CTLA-4 on costimulation.