Understanding repertoire sequencing data through a multiscale computational model of the germinal center

Abstract

Abstract Sequencing of B cell and T cell immune receptor repertoires helps us to understand the adaptive immune response, although it only provides information about the clonotypes and their frequencies. Generally, additional time-consuming or expensive experiments are required to further characterize the identified (dominant) clones by measuring, for example, their affinity or function. Here, we present a multiscale model of the germinal center (GC) to gain general insight in B cell repertoires, to establish the relationship between clonal abundance and affinity, to establish the variability of affinity within a clone, and to establish the extent that plasma cells (PCs) with high B cell receptor (BcR) mRNA content may disturb the identification of dominant clones. Since we simulate B cell repertoires generated from a single GC we also compare the extent that these repertoires deviate from experimental repertoires established from single GCs, blood or tissue. Our simulations show that there is a limited correlation between clonal abundance and affinity and that there is large affinity variability among same-ancestor subclones. Our simulations suggest that low abundant (sub)clones might also be of interest since they may have high affinity for the Ag. We show that the presence of PCs does not significantly affect the number of dominant clones derived from single GCs by sequencing BcR mRNAs. As expected, immune repertoires generated from our single GC model deviate in several aspects from experimental repertoires. At the same time, results from these simulations guide data interpretation and the design of follow-up experiments.