Potent T cell activation with dimeric peptide major histocompatibility complex class II ligand: The role of CD4 coreceptor
Potent T cell activation with dimeric peptide major histocompatibility complex class II ligand: The role of CD4 coreceptor
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DOI：
10.1084/jem.188.9.1633
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发表时间：
1998-11-02
影响因子：
15.3
通讯作者：
Pardoll, D
中科院分区：
文献类型：
--
作者：
Hamad, ARA;O'Herrin, SM;Pardoll, D
T细胞受体（TCR）与其在抗原呈递细胞（APCs）表面的同源肽 - 主要组织相容性复合体（MHC）的相互作用是T细胞活化过程中的一个主要事件。在此我们使用二聚体IEk - MCC分子来研究其激活抗原特异性T细胞的能力，并直接分析CD4在物理上稳定TCR - MHC相互作用中的作用。二聚体IEk - MCC稳定地结合到特异性T细胞上。此外，固定化的二聚体IEk - MCC能够诱导TCR下调，并且比抗CD8更有效地激活抗原特异性T细胞。在CD4存在的情况下，二聚体IEk - MCC的效力显著增强。然而，CD4在稳定肽 - MHC - TCR相互作用方面没有起到任何显著作用，因为它不能增强IEk - MCC与特异性T细胞的结合，也不能影响肽 - MHC - TCR的解离速率或TCR下调。而且，这些结果表明，使用IgG分子支架使肽 - MHC II类二聚化显著增加了其结合亲和力，从而提高了其刺激能力，同时保持了同源肽 - MHC复合物的生理特性。因此，这些肽 - MHC - IgG嵌合体可能为在体外和体内调节抗原特异性T细胞反应提供一种新的方法。
The interaction of the T cell receptor (TCR) with its cognate peptide-major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) is a primary event during T cell activation. Here we used a dimeric IEk-MCC molecule to study its capacity to activate antigen-specific T cells and to directly analyze the role of CD4 in physically stabilizing the TCR-MHC interaction. Dimeric IEk-MCC stably binds to specific T cells. In addition, immobilized dimeric IEk-MCC can induce TCR downregulation and activate antigen-specific T cells more efficiently than anti-CDS. The potency of the dimeric IEk-MCC is significantly enhanced in the presence of CD4. However, CD4 does not play any significant role in stabilizing peptide-MHC-TCR interactions as it fails to enhance binding of IEk-MCC to specific T cells or influence peptide-MHC-TCR dissociation rate or TCR downregulation. Moreover, these results indicate that dimerization of peptide-MHC class II using an IgG molecular scaffold significantly increases its binding avidity leading to an enhancement of its stimulatory capacity while maintaining the physiological properties of cognate peptide-MHC complex. These peptide-MHC-IgG chimeras may, therefore, provide a novel approach to modulate antigen-specific T cell responses both in vitro and in vivo.