“GOD” Mode: Generation of Diversity in BCRs and TCRs

Complementarity-determining regions (CDRs) are the hypervariable regions within the variable domains of B-cell receptors (BCRs) and T-cell receptors (TCRs) that directly interact with and bind to antigenic peptides or proteins. These regions play a crucial role in determining the specificity of antigen recognition by BCRs and TCRs.

The CDRs are found within the variable (V) domains of the receptor proteins, not the constant (C) domains. For BCRs, there are 3 CDRs (CDR1, CDR2, CDR3) in the V region of both the heavy and light chains. Similarly, for TCRs, there are 3 CDRs (CDR1, CDR2, CDR3) in the V region of both the alpha and beta (or gamma and delta) chains.

The CDR1 and CDR2 are encoded entirely within the V gene segment sequences. The CDR3 is the most diverse and is formed by the junction of the rearranged V, D (for some chains), and J gene segments during V(D)J recombination.

This focused diversity in the CDR loops, especially CDR3, allows the generation of a tremendously varied antibody and TCR repertoire capable of recognizing a vast array of different antigenic structures and epitopes.

Summary of Diversity Mechanism So Far…and Hints of Diversification Mechanisms Yet to Be Discussed

The generation of a highly diverse repertoire of antigen receptors on lymphocytes (B cells and T cells) is critical for the ability of the adaptive immune system to recognize and respond to a vast array of different pathogens and foreign molecules. This diversity is achieved through several mechanisms:

V(D)J Recombination

This is the primary mechanism generating receptor diversity. During lymphocyte development, one V, (D), and J gene segment is randomly selected and rearranged from the set of germline V, D, and J genes to encode the variable domain. The combinatorial rearrangement of these gene segments provides an initial diversity of millions of receptor specificities.

Junctional Diversity

Further diversity is added at the V(D)J junctions due to imprecise joining of the gene segments, creating insertions and deletions of nucleotides. This junctional diversity exponentially increases the number of possible receptor sequences, especially in the CDR3 region.

N Region Addition

Enzyme terminal deoxynucleotidyl transferase can randomly add non-templated (N) nucleotides at the V(D)J junctions, adding another layer of junctional diversity.

Combinatorial Diversity

For B cells, the pairing of different heavy and light chain combinations contributes to increased diversity of the BCR repertoire.

Gene Conversion

In some species like chickens, gene conversion of V gene segments with upstream pseudogenes creates additional V region sequence diversity.

Somatic Hypermutation (BCRs only)

After antigen encounter, activation-induced cytidine deaminase triggers somatic hypermutation in BCR genes. Point mutations accumulate in the V regions, allowing affinity maturation.

Through these multiple diversification mechanisms operating at different stages, the theoretical diversity of BCR/TCR specificities is estimated to be 10^12 to 10^18 unique receptors per individual, ensuring coverage of virtually any potential antigen.

End of Section 4.1

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Source: Claude 3 Sonnet response prompted and edited by Joel Graff.

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