Models for antigen receptor gene rearrangement: CDR3 length

Abstract

Despite the various processing steps involved in V(D)J recombination, which could potentially introduce many biases in the length distribution of complementarity determining region 3 (CDR3) segments, the observed CDR3 length distributions for complete repertoires are very close to a normal-like distribution. This raises the question of whether this distribution is simply a result of the random steps included in the process of gene rearrangement, or has been optimized during evolution. We have addressed this issue by constructing a simulation of gene rearrangement, which takes into account the DNA modification steps included in the process, namely hairpin opening, nucleotide additions, and nucleotide deletions. We found that the near-Gaussian-shape of CDR3 length distribution can only be obtained under a relatively narrow set of parameter values, and thus our model suggests that specific biases govern the rearrangement process. In both B-cell receptor (BCR) heavy chain and T-cell receptor b chain, we obtained a Gaussian distribution using identical parameters, despite the difference in the number and the lengths of the D segments. Hence our results suggest that these parameters most likely reflect the optimal conditions under which the rearrangement process occurs. We have subsequently used the insights gained in this study to estimate the probability of occurrence of two exactly identical BCRs over the course of a human lifetime. Whereas identical rearrangements of the heavy chain are highly unlikely to occur within one human lifetime, for the light chain we found that this probability is not negligible, and hence the light chain CDR3 alone cannot serve as an indicator of B-cell clonality. To cope with the wide range of pathogens encountered during a lifetime, B and T lymphocytes express a diverse repertoire of binding specificities, in the form of B-cell antigen receptors or secreted antibodies, also called immunoglobulins (Ig), in B-cells (BCR), or T-cell receptors (TCR) in T cells. Each B-or T cell expresses a singleantigen specificity, determined early in its differentiation, when the genes encoding the variable regions of Ig heavy and light chains (or TCRb-and -a chains, respectively) are rearranged from gene segments. [1][2][3][4][5][6][7][8][9][10][11] In the BCR light chain or TCRa chain, each V domain is encoded by two separate DNA segments, the V gene segment and the joining or J gene segment. In the BCR heavy chain or TCRb chain V regions, there is a third gene segment called the diversity or D gene segment, which lies between V and J segments. There are multiple copies of V, D, and J gene segments within each receptor gene locus. Sequence variability is not evenly distributed throughout the V region; three areas of particular variability can be identified in both heavy/band light/a chain, designated hypervariable regions. As the three hypervariable loops constitute the binding site for antigen and determine specificity by forming a surface complementary to the antigen, they are more commonly termed t...

Investigating the effect of AS03 adjuvant on the plasma cell repertoire following pH1N1 influenza vaccination

“…Co-clustering the data from the TIV and pH1N1 datasets for each participant revealed that on average 52 clusters were shared between their TIV and pH1N1 plasma cell datasets, equating to 1% of the total number of clusters present in the two datasets. As the probability of the same CDR3 being produced during two independent recombination events during the lifetime of a single individual is practically zero, it is likely that these shared clusters represent memory recall of the same B cell lineage1628. On average, 98% of these recalled clusters were classed as mutated following pH1N1 vaccination, compared to 88% of total clusters (p  =  0.0002; Fig.…”

“…To study recalled clusters that are likely to be influenza-specific, those present in the TIV dataset, that then re-appear in the pH1N1 dataset were found for each participant. As the probability of the same CDR3 being produced during two independent recombination events during the lifetime of a single individual is practically zero, it is likely that these shared clusters represent memory recall of the same B cell lineage1628. On average, there were 52 clusters for each participant found in both the TIV and pH1N1 datasets, equating to approximately 1% of the total number of clusters present in the two datasets.…”

Immune Responses Are Characterized by Specific Shared Immunoglobulin Peptides That Can Be Detected by Proteomic Techniques*

“…Estimates on the total possible diversity in immunoglobulins vary depending on the assumptions being made, ranging from 10 13 to more than 10 50 (2,3). Despite the large range, it is sufficiently clear that sequence variation is large, and based on these numbers one could statistically assume that antibody sequences found in a person must be unique, and that such antibodies will not be found in other subjects.…”

Peptides from the Variable Region of Specific Antibodies Are Shared among Lung Cancer Patients

“…Antibodies, or immunoglobulins, are highly complex molecules with large variation in their amino acid sequence. The possible diversity in immunoglobulins is estimated between 10 13 and 10 50 and therefore the finding of similar or even identical sequences in different individuals by chance is in theory, highly unlikely [14], [15]. However, studies of different research groups have recently demonstrated that despite this theoretical small chance to have identical antibodies among individuals, it is possible to identify similar or identical sequences [16]–[19].…”