Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
PLoS One. 2013 Sep 10;8(9):e73610. doi: 10.1371/journal.pone.0073610. eCollection 2013.
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.
大多数针对病原体或自身抗原的 T 细胞反应都是通过调节性 T 细胞和组织特异性抑制机制来调节的。为此，已经进化出了几种受体-配体对，它们可以增强或减弱 T 细胞的功能。在这里，我们将描述组织配体 SECTM1A（分泌型和跨膜 1A）作为一种替代的鼠 CD7 配体。我们表明，SECTM1A 像 SECTM1B 一样，与 CD7 强烈结合，并且 SECTM1B 能够与 SECTM1A 竞争 CD7 结合。SECTM1A 广泛表达，并且有两种主要的替代转录本，它们在组织之间的表达不同。固定化可溶性形式的 SECTM1A 和 SECTM1B 以及细胞表面锚定形式均对 CD4+T 细胞的激活表现出相反的影响。尽管 SECTM1A 作为 T 细胞的共刺激物起作用，增强了 IL-2 的产生和增殖，但 SECTM1B 被证明对 TCR 介导的 T 细胞激活具有抑制作用。令人惊讶的是，这两种功能结果都被证明与 CD7 无关，这表明这两种配体都存在替代受体。我们使用 SECTM1A-Fc 融合蛋白从 CD7(-/-)T 细胞的去污剂裂解物中免疫沉淀潜在的替代配体，并使用质谱法鉴定 GITR 为 SECTM1A 的结合物。发现 SECTM1A 与激活的 CD4+和 CD8+T 细胞以及表达细胞表面 GITR 的 CHO 细胞结合。SECTM1A 与激活的原代 T 细胞的结合被 GITRL-Fc 或抗 GITR 抗体抑制。因此，SECTM1A 和 SECTM1B 代表新的相互替代的配体，它们可能调节效应器和调节性 T 细胞的激活。SECTM1A 激活 T 细胞的能力可以通过其与 GITR 结合的能力来解释。
