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CTLA-4 up-regulation plays a role in tolerance mediated by CD45.
Nature Immunology ( IF 30.5 ) Pub Date : 2001-03-29 , DOI: 10.1038/83175
S Fecteau 1 , G P Basadonna , A Freitas , C Ariyan , M H Sayegh , D M Rothstein
Affiliation  

Cytolytic T lymphocyte-associated antigen 4 (CTLA-4) is a critical down-regulatory molecule in T cells that plays a major role in peripheral tolerance. Although the CD45 protein tyrosine phosphatase is a potent immunomodulatory target, the mechanisms by which antibody against CD45RB isoforms (anti-CD45RB) induces allograft tolerance remain unclear. We show here that anti-CD45RB treatment alters CD45 isoform expression on T cells, which is associated with rapid up-regulation of CTLA-4 expression. These effects appear specific and occur without up-regulation of other activation markers. Administration of a blocking monoclonal antibody to CTLA-4 at the time of transplantation prevents anti-CD45RB therapy from prolonging islet allograft survival. In addition, treatment with cyclosporin A blocks anti-CD45RB-induced CTLA-4 expression and promotes acute rejection. These data suggest that anti-CD45RB acts through mechanisms that include CTLA-4 up-regulation and demonstrate a link between CD45 and CTLA-4 that depends on calcineurin-mediated signaling. They demonstrate also that CTLA-4 expression may be specifically targeted to enhance allograft acceptance.

中文翻译:

CTLA-4上调在CD45介导的耐受中发挥作用。

细胞溶解性T淋巴细胞相关抗原4(CTLA-4)是T细胞中的关键下调分子,在外周耐受中起主要作用。尽管CD45蛋白酪氨酸磷酸酶是有效的免疫调节靶标,但针对CD45RB亚型的抗体(抗CD45RB)诱导同种异体移植耐受性的机制仍不清楚。我们在这里显示抗CD45RB治疗改变T细胞上CD45亚型的表达,这与CTLA-4表达的快速上调有关。这些作用似乎是特异性的,并且在没有其他激活标记上调的情况下发生。在移植时给予CTLA-4封闭性单克隆抗体可防止抗CD45RB治疗延长同种异体胰岛存活。此外,环孢菌素A治疗可阻断抗CD45RB诱导的CTLA-4表达并促进急性排斥反应。这些数据表明抗CD45RB通过包括CTLA-4上调的机制起作用,并证明CD45和CTLA-4之间的联系依赖于钙调神经磷酸酶介导的信号传导。他们还证明了CTLA-4表达可能是专门针对增强同种异体移植接受性的。
更新日期:2019-11-01
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