Immunoglobulin divalence promotes B-cell antigen receptor cluster scale-dependent functions

Area of Science:

• Immunology
• Cell Biology
• Structural Biology

Background:

• Antibodies (immunoglobulins) possess a conserved dimeric structure with two antigen-binding sites.
• Monovalent binding domains are sufficient for molecular recognition in other immune receptors, questioning the necessity of immunoglobulin divalence.
• Immunoglobulins function as soluble effectors and as membrane-bound B-cell antigen receptors (BCRs).

Purpose of the Study:

• To investigate the functional significance of immunoglobulin divalence in B-cell antigen receptor (BCR) signaling.
• To determine the role of BCR clustering and valence in cellular signaling and antigen internalization.
• To elucidate the mechanism by which BCRs translate clustering status into cellular responses.

Main Methods:

• Generation of monovalent BCRs for functional assays.
• Advanced superresolution imaging of BCRs upon antigen stimulation.
• Analysis of intracellular signaling and antigen internalization capabilities.

Main Results:

• Monovalent BCRs exhibited significantly impaired signaling and antigen internalization.
• Receptor cluster scale in the plasma membrane directly correlates with the magnitude of intracellular signaling.
• Increased ITAMs in single BCRs led to desensitization rather than enhanced sensitivity.
• BCR signaling machinery is sensitive to receptor clustering status and translates cluster size into cellular responses.

Conclusions:

• Immunoglobulin divalence is crucial for optimal BCR function, particularly for signaling and antigen uptake.
• BCR-mediated signaling is regulated by the scale and clustering of receptors on the cell surface.
• These findings provide insights into adaptive immune receptor function and inform the design of chimeric antigen receptors.