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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
Alfreda D. Nelson Alfreda D. Nelson 1*Liangyu Wang Liangyu Wang 2Kimberly G. Laffey Kimberly G. Laffey 2Laura R. Becher Laura R. Becher 3Christopher A. Parks Christopher A. Parks 3*Michele M. Hoffmann Michele M. Hoffmann 3*Belinda K. Galeano Belinda K. Galeano 3Ashutosh K. Mangalam Ashutosh K. Mangalam 4Emma Teixeiro Emma Teixeiro 2Tommi A. White Tommi A. White 5*Adam G. Schrum Adam G. Schrum 2*John F. Cannon John F. Cannon 2*Diana Gil Pagés Diana Gil Pagés 2*
  • 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

The final, formatted version of the article will be published soon.

    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

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.