Secreted and transmembrane 1A is a novel co-stimulatory ligand.
Secreted and transmembrane 1A is a novel co-stimulatory ligand.
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DOI：
10.1371/journal.pone.0073610
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Waldmann H
中科院分区：
文献类型：
--
作者：
Howie D;Garcia Rueda H;Brown MH;Waldmann H
大多数T细胞对病原体或自身抗原的反应是通过调节性T细胞和组织特异性抑制机制来调节的。为此，一些受体-配体对已经进化出来，它们要么增强要么削弱T细胞的功能。在这里，我们描述了组织配体SECTM1A(分泌型和跨膜型)作为一种替代的小鼠CD7配体。我们发现SECTM1A和SECTM1B一样，与CD7结合很强，并且SECTM1B能够与SECTM1A竞争CD7结合。SECTM1a广泛表达，有两个主要的可供选择的转录本，在不同的组织中表达不同。SECTM1A和SECTM1B的固定化可溶性形式和细胞表面锚定形式对CD4+T细胞的激活都显示出相反的作用。SECTM1A作为T细胞的共刺激因子，促进IL-2的产生和增殖，而SECTM1B则对TCR介导的T细胞活化有抑制作用。令人惊讶的是，这两种功能结果都被证明是CD7不依赖的，这表明两种配体都存在替代受体。我们使用SECTM1AFc融合蛋白从CD7CD7GITR T细胞的洗涤剂裂解液中免疫沉淀潜在的替代配体，并通过质谱仪鉴定GITR是SECTM1A型结合蛋白。SECTM1a可与活化的CD4+和CD8+T细胞结合，也可与表达细胞表面GITR的CHO细胞结合。GITRL-Fc或抗GITR抗体均可抑制SECTM1a与活化的原代T细胞的结合。因此，SECTM1A和SECTM1B代表了新的相互替代的配体，其功能可能是调节效应T细胞和调节性T细胞的激活。SECTM1A激活T细胞的能力可能与其与GITR结合的能力有关。
Most T cell responses to pathogens or self antigens are modulated through the action of regulatory T cells and tissue-specific inhibitory mechanisms. To this end, several receptor-ligand pairs have evolved which either augment or diminish T cell function. Here we describe the tissue ligand SECTM1A (Secreted and transmembrane1A) as an alternative murine CD7 ligand. We show that SECTM1A, like SECTM1B, binds strongly to CD7, and that SECTM1B was able to compete with SECTM1A for CD7 binding. SECTM1A is ubiquitously expressed and has two major alternative transcripts which differ in expression between tissues. Both immobilised soluble forms of SECTM1A and SECTM1B and cell surface anchored forms demonstrated opposing effects on CD4+ T cell activation. Whereas SECTM1A acted as a co-stimulator of T cells, enhancing IL-2 production and proliferation, SECTM1B proved inhibitory to TCR mediated T cell activation. Surprisingly, both functional outcomes proved to be CD7-independent, indicating the existence of alternative receptors for both ligands. We used a SECTM1A-Fc fusion protein to immunoprecipitate potential alternative ligands from detergent lysates of CD7−/− T cells and, using mass spectrometry, identified GITR as a SECTM1A binder. SECTM1A was found to bind to activated CD4+ and CD8+ T cells as well as to CHO cells expressing cell surface GITR. Binding of SECTM1A to activated primary T cells was inhibited by either GITRL-Fc or anti GITR antibodies. Thus SECTM1A and SECTM1B represent novel reciprocal alternative ligands which may function to modulate the activation of effector and regulatory T cells. The ability of SECTM1A to activate T cells may be explained by its ability to bind to GITR.
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影响因子：
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作者：
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