An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells
An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells
复制标题
DOI：
10.1016/s1074-7613(04)00110-4
复制
发表时间：
2004-05-01
期刊：
影响因子：
32.4
通讯作者：
Kuchroo, VK
中科院分区：
文献类型：
--
作者：
Vijayakrishnan, L;Slavik, JM;Kuchroo, VK
细胞毒性T淋巴细胞相关抗原-4(CTLA-4)在下调T细胞应答中起关键作用。许多自身免疫性疾病已经显示出与CTLA-4基因座的遗传连锁。我们已经在NOD小鼠中克隆并表达了一种与I型糖尿病有遗传联系的选择性剪接形式的CTLA-4。CTLA-4的这种剪接变体被称为配体非依赖性CTLA-4(liCTLA-4)，它缺少外显子2，包括与共刺激配体B7-1和B7-2结合所必需的MYPPPY基序。在这里，我们证明了liCTLA-4在原代T细胞中以蛋白质的形式表达，并通过结合和去磷酸化TcRzeta链来强烈地抑制T细胞的反应。与易感NOD小鼠相比，糖尿病耐药NOD同源小鼠的记忆/调节T细胞表达liCTLA-4，而不是全长CTLA-4(fICTLA-4)。这些数据表明，由liCTLA-4传递的表达增加和负信号可能调节T细胞介导的自身免疫性疾病的发展。
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) plays a critical role in downregulating T cell responses. A number of autoimmune diseases have shown genetic linkage to the CTLA-4 locus. We have cloned and expressed an alternatively spliced form of CTLA-4 that has genetic linkage with type I diabetes in the NOD mice. This splice variant of CTLA-4, named ligand-independent CTLA-4 (liCTLA-4), lacks exon2 including the MYPPPY motif essential for binding to the costimulatory ligands B7-1 and B7-2. Here we show that liCTLA-4 is expressed as a protein in primary T cells and strongly inhibits T cell responses by binding and dephosphorylating the TcRzeta chain. Expression of liCTLA-4, but not full-length CTLA-4 (fICTLA-4), was higher in memory/regulatory T cells from diabetes-resistant NOD congenic mice compared to susceptible NOD mice. These data suggest that increased expression and negative signaling delivered by the liCTLA-4 may regulate development of T cell-mediated autoimmune diseases.