Current strategies for detecting functional convergence across B-cell receptor repertoires

Abstract

Convergence across B-cell receptor (BCR) and antibody repertoires has become instrumental in prioritizing candidates in recent rapid therapeutic antibody discovery campaigns. It has also increased our understanding of the immune system, providing evidence for the preferential selection of BCRs to particular (immunodominant) epitopes post vaccination/infection. These important implications for both drug discovery and immunology mean that it is essential to consider the optimal way to combine experimental and computational technology when probing BCR repertoires for convergence signatures. Here, we discuss the theoretical basis for observing BCR repertoire functional convergence and explore factors of study design that can impact functional signal. We also review the computational arsenal available to detect antibodies with similar functional properties, highlighting opportunities enabled by recent clustering algorithms that exploit structural similarities between BCRs. Finally, we suggest future areas of development that should increase the power of BCR repertoire functional clustering.

Keywords: BCR repertoire; BCR-seq; Ig-seq; antibody; clonal clustering; evolution; function; selection; sequencing; structural clustering.

Figure 1.

The concepts of functional convergence/epitope immunodominance. Each individual possesses in the region of 10⁹ naive B-cells together sampling a wide range of B-cell receptors (BCRs). Upon antigen exposure, some of these ‘baseline’ BCRs will be sufficiently complementary to various epitopes (shown as a rectangle, triangle, and circle) on the antigen surface and will initiate an immune response. In this example, BCRs exist across the two different individuals that can recognize the “circle” epitope – they have BCR repertoire functional commonality. After differentiation into plasma cells and affinity maturation, the resulting antibody repertoires can also be seen to converge around specificity to this epitope. The “circle” epitope is therefore ‘immunodominant’ over the other two epitopes, since it was the one was able to engender an immune response in both individuals

Figure 2.

The many experimental parameters that can influence the functional signal in BCR-seq data, spanning the broad categories of blood donor recruitment, B-cell sampling and sorting, and B-cell sequencing and sequence processing