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CD3复合物的刚性交联导致卓越的T细胞刺激。

Rigid crosslinking of the CD3 complex leads to superior T cell stimulation.

作者信息

Nelson Alfreda D, Wang Liangyu, Laffey Kimberly G, Becher Laura R E, Parks Christopher A, Hoffmann Michele M, Galeano Belinda K, Mangalam Ashutosh, Teixeiro Emma, White Tommi A, Schrum Adam G, Cannon John F, Gil Diana

机构信息

Department of Surgery, School of Medicine, University of Missouri, Columbia, MO, United States.

Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, United States.

出版信息

Front Immunol. 2024 Aug 30;15:1434463. doi: 10.3389/fimmu.2024.1434463. eCollection 2024.

DOI:10.3389/fimmu.2024.1434463
PMID:39281668
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11392757/
Abstract

Functionally bivalent non-covalent Fab dimers (Bi-Fabs) specific for the TCR/CD3 complex promote CD3 signaling on T cells. While comparing functional responses to stimulation with Bi-Fab, F(ab')2 or mAb specific for the same CD3 epitope, we observed fratricide requiring anti-CD3 bridging of adjacent T cells. Surprisingly, anti-CD3 Bi-Fab ranked first in fratricide potency, followed by anti-CD3 F(ab')2 and anti-CD3 mAb. Low resolution structural studies revealed anti-CD3 Bi-Fabs and F(ab')2 adopt similar global shapes with CD3-binding sites oriented outward. However, under molecular dynamic simulations, anti-CD3 Bi-Fabs crosslinked CD3 more rigidly than F(ab')2. Furthermore, molecular modelling of Bi-Fab and F(ab')2 binding to CD3 predicted crosslinking of T cell antigen receptors located in opposing plasma membrane domains, a feature fitting with T cell fratricide observed. Thus, increasing rigidity of Fab-CD3 crosslinking between opposing effector-target pairs may result in stronger T cell effector function. These findings could guide improving clinical performance of bi-specific anti-CD3 drugs.

摘要

针对TCR/CD3复合物的功能性双价非共价Fab二聚体（双特异性Fab，Bi-Fab）可促进T细胞上的CD3信号传导。在比较用针对相同CD3表位的Bi-Fab、F(ab')2或单克隆抗体（mAb）刺激后的功能反应时，我们观察到相邻T细胞的自相残杀需要抗CD3的桥接。令人惊讶的是，抗CD3 Bi-Fab在自相残杀效力方面排名第一，其次是抗CD3 F(ab')2和抗CD3 mAb。低分辨率结构研究表明，抗CD3 Bi-Fab和F(ab')2具有相似的整体形状，CD3结合位点向外。然而，在分子动力学模拟中，抗CD3 Bi-Fab比F(ab')2更刚性地交联CD3。此外，Bi-Fab和F(ab')2与CD3结合的分子模型预测，位于相对质膜结构域的T细胞抗原受体发生交联，这一特征与观察到的T细胞自相残杀相符。因此，增加相对效应细胞-靶细胞对之间Fab-CD3交联的刚性可能导致更强的T细胞效应功能。这些发现可为提高双特异性抗CD3药物的临床性能提供指导。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d23/11392757/ae1bfb9bccc9/fimmu-15-1434463-g014.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d23/11392757/bc1fe66187a1/fimmu-15-1434463-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d23/11392757/ae1bfb9bccc9/fimmu-15-1434463-g014.jpg

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