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ORIGINAL RESEARCH article
Front. Immunol.
Sec. T Cell Biology
Volume 15 - 2024 |
doi: 10.3389/fimmu.2024.1434463
Rigid crosslinking of the CD3 complex leads to superior T cell stimulation
Provisionally accepted- 1 Department of Surgery, University of Missouri, Columbia, United States
- 2 Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, United States
- 3 Department of Immunology, College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, United States
- 4 Department of Pathology, The University of Iowa, Iowa City, Iowa, United States
- 5 Department of Biochemistry, University of Missouri, Columbia, United States
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.
Keywords: T cell receptor engagement and triggering, Antibody fragment structure, CD3/Antibody crosslinking, T cell division and apoptosis, Anti-CD3 Fab-based therapies, EAE (experimental autoimmune encephalomyelitis), Molecular dynamic simulation
Received: 17 May 2024; Accepted: 07 Aug 2024.
Copyright: © 2024 Nelson, Wang, Laffey, Becher, Parks, Hoffmann, Galeano, Mangalam, Teixeiro, White, Schrum, Cannon and Gil Pagés. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Alfreda D. Nelson, Department of Surgery, University of Missouri, Columbia, United States
Christopher A. Parks, Department of Immunology, College of Medicine and Science, Mayo Clinic, Rochester, 55905-0001, Minnesota, United States
Michele M. Hoffmann, Department of Immunology, College of Medicine and Science, Mayo Clinic, Rochester, 55905-0001, Minnesota, United States
Tommi A. White, Department of Biochemistry, University of Missouri, Columbia, United States
Adam G. Schrum, Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, United States
John F. Cannon, Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, United States
Diana Gil Pagés, Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, United States
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