Bibliographic Details
| Title: |
Rigid crosslinking of the CD3 complex leads to superior T cell stimulation |
| Authors: |
Alfreda D. Nelson, Liangyu Wang, Kimberly G. Laffey, Laura R. E. Becher, Christopher A. Parks, Michele M. Hoffmann, Belinda K. Galeano, Ashutosh Mangalam, Emma Teixeiro, Tommi A. White, Adam G. Schrum, John F. Cannon, Diana Gil |
| Source: |
Frontiers in Immunology, Vol 15 (2024) |
| Publisher Information: |
Frontiers Media S.A., 2024. |
| Publication Year: |
2024 |
| Collection: |
LCC:Immunologic diseases. Allergy |
| Subject Terms: |
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), Immunologic diseases. Allergy, RC581-607 |
| More Details: |
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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1664-3224 |
| Relation: |
https://www.frontiersin.org/articles/10.3389/fimmu.2024.1434463/full; https://doaj.org/toc/1664-3224 |
| DOI: |
10.3389/fimmu.2024.1434463 |
| Access URL: |
https://doaj.org/article/e0c851df2d934c47ad596fb4db81592c |
| Accession Number: |
edsdoj.0c851df2d934c47ad596fb4db81592c |
| Database: |
Directory of Open Access Journals |
