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The evolutionary and structural 'logic' of antigen receptor diversity
1The Department of Microbiology and Immunology, Stanford University School of Medicine, The Howard Hughes Medical Institute, 279 Campus Drive, Stanford, CA 94305-5323, USA. mdavis@cmgm.stanford.edu
Seminars in Immunology
|November 4, 2004
Summary
Vertebrates use diverse CDR3 regions in antigen receptors for specificity. Somatic hypermutation refines antibody affinity, suggesting CDR3 diversity is key, not V region repertoire variation.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Vertebrates generate diverse antigen receptors (antibodies, T-cell receptors) using variable gene segments.
- A common feature is a highly diverse CDR3 region, crucial for antigen binding.
- Existing models struggle to explain this CDR3 diversity pattern in all receptor types.
Purpose of the Study:
- To investigate the role of CDR3 diversity in antigen receptor function.
- To test a bipartite binding site model for antigen receptors.
- To understand the interplay between primary repertoire diversity and somatic hypermutation.
Main Methods:
- Engineering mice with a limited V region repertoire.
- Generating and analyzing primary antibodies with identical V regions but diverse CDR3s.
- Assessing antibody specificity and affinity after immunization and somatic hypermutation.
Main Results:
- Primary antibodies with identical V regions but diverse CDR3s demonstrated high antigen specificity.
- Repeated immunization led to high-affinity antibodies, indicating successful affinity maturation.
- The V(H) CDR3 sequence was critical for primary antigen recognition.
Conclusions:
- Antigen receptor binding sites likely utilize a bipartite model with a diverse CDR3 core.
- Somatic hypermutation effectively enhances antibody affinity from low-affinity precursors.
- Preservation of diverse CDR3 regions is more critical than overall V region repertoire diversity across vertebrates.