The human naive T-cell receptor (TCR) repertoire is extremely diverse and accurately estimating its distribution is challenging. We address this challenge by combining a quantitative sequencing protocol of TCRA and TCRB sequences with computational modeling. We observed the vast majority of TCR chains only once in our samples, confirming the enormous diversity of the naive repertoire. However, a substantial number of sequences were observed multiple times within samples, and we confirmed that this was due to high abundance in the naive pool, rather than high mRNA levels. We reason that alpha and beta chains become abundant due to a combination of selective processes and summation over multiple clones expressing these chains. We test the contribution of both mechanisms by predicting samples from phenomenological and mechanistically modeled repertoire distributions. By comparing these with sequencing data, we show that most abundant chains are likely to be derived from multiple clones. Still, a neutral model of T-cell homeostasis cannot account for the observed distributions. We conclude that the data are only compatible with distributions of many small clones in combination with a sufficient number of very large naive T-cell clones, most likely as a result of strong peripheral selection.
This event is part of the Physiology Friday Seminar Series and is co-sponsored by CAMBAM.