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Rigid crosslinking of the CD3 complex leads to superior T cell stimulation
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Rigid crosslinking of the CD3 complex leads to superior T cell stimulation
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Journal Article
Rigid crosslinking of the CD3 complex leads to superior T cell stimulation
2024
Overview
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.
Publisher
Frontiers Media SA,Frontiers Media S.A
Subject
/ anti-CD3 Fab-based therapies
/ Antibodies, Monoclonal - immunology
/ Antigens
/ EAE (experimental autoimmune encephalomyelitis)
/ Epitopes
/ Fab
/ Humans
/ Immunoglobulin Fab Fragments - chemistry
/ Immunoglobulin Fab Fragments - immunology
/ Immunoglobulin Fab Fragments - metabolism
/ Ligands
/ Lymphocyte Activation - immunology
/ Mice
/ Molecular Dynamics Simulation
/ Plasma
/ Receptor-CD3 Complex, Antigen, T-Cell - immunology
/ Receptor-CD3 Complex, Antigen, T-Cell - metabolism
/ Receptors, Antigen, T-Cell - immunology
/ Receptors, Antigen, T-Cell - metabolism
/ T cell division and apoptosis
/ T cell receptor engagement and triggering
/ Tumors
