The Shape of the Lymphocyte Receptor Repertoire: Lessons from the B Cell Receptor

Abstract

Both the B cell receptor (BCR) and the T cell receptor (TCR) repertoires are generated through essentially identical processes of V(D)J recombination, exonuclease trimming of germline genes, and the random addition of non-template encoded nucleotides. The naïve TCR repertoire is constrained by thymic selection, and TCR repertoire studies have therefore focused strongly on the diversity of MHC-binding complementarity determining region (CDR) CDR3. The process of somatic point mutations has given B cell studies a major focus on variable (IGHV, IGLV, and IGKV) genes. This in turn has influenced how both the naïve and memory BCR repertoires have been studied. Diversity (D) genes are also more easily identified in BCR VDJ rearrangements than in TCR VDJ rearrangements, and this has allowed the processes and elements that contribute to the incredible diversity of the immunoglobulin heavy chain CDR3 to be analyzed in detail. This diversity can be contrasted with that of the light chain where a small number of polypeptide sequences dominate the repertoire. Biases in the use of different germline genes, in gene processing, and in the addition of non-template encoded nucleotides appear to be intrinsic to the recombination process, imparting “shape” to the repertoire of rearranged genes as a result of differences spanning many orders of magnitude in the probabilities that different BCRs will be generated. This may function to increase the precursor frequency of naïve B cells with important specificities, and the likely emergence of such B cell lineages upon antigen exposure is discussed with reference to public and private T cell clonotypes.

Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires

“…Promiscuous light-chain sequences (i.e., light chains paired with two or more VH sequences) have been observed previously and result from the lower diversity of light-chain Vκ,λ-Jκ,λ junctions (6,29). We found widespread evidence of promiscuous light-chain junctions, i.e., Vκ,λ-Jκ,λ junctions observed in multiple BCRs within the same donor.…”

“…Understanding the salient features of the human antibody repertoire is critical for immunology research (6,7). Specifically, additional information is needed regarding how a history of pathogen and environmental exposure modulates the sequence and conformational properties of naive antibodies to yield a mature antibody repertoire that confers effective protection.…”

Complexity of the human memory B-cell compartment is determined by the versatility of clonal diversification in germinal centers

“…Third, how diverse is the pool of memory B cells generated from a GC B-cell clone in terms of intraclonal IgV gene diversity, and how large can memory B-cell clones be? Next-generation sequencing (NGS) of IgV genes allows a comprehensive overview on the composition and diversity of the lymphocyte compartment (23)(24)(25)(26). Several previous studies already analyzed human IGHV gene repertoire diversity.…”

The mouse antibody heavy chain repertoire is germline-focused and highly variable between inbred strains

“…Antibody diversity is expanded still further by junctional diversification arising from the incorporation of P nucleotides derived from the opening of hairpin loops that form at gene ends as part of the rearrangement process, from exonuclease trimming of the recombining gene ends, and from the essentially random addition of N nucleotides between the recombining genes [3]. The permutations of recombining gene segments, the generation of junctional diversity and the permutations of associating heavy and light chain pairs together give the immune system the capacity to produce billions of different antibody molecules [4].…”