Population variability in the generation and selection of T-cell repertoires.

Zachary Sethna,Aleksandra M. Walczak,Thomas Dupic,Yuval Elhanati,Thierry Mora,Giulio Isacchini,Benny Chain

doi:10.1371/journal.pcbi.1008394

Abstract

The diversity of T-cell receptor (TCR) repertoires is achieved by a combination of two intrinsically stochastic steps: random receptor generation by VDJ recombination, and selection based on the recognition of random self-peptides presented on the major histocompatibility complex. These processes lead to a large receptor variability within and between individuals. However, the characterization of the variability is hampered by the limited size of the sampled repertoires. We introduce a new software tool SONIA to facilitate inference of individual-specific computational models for the generation and selection of the TCR beta chain (TRB) from sequenced repertoires of 651 individuals, separating and quantifying the variability of the two processes of generation and selection in the population. We find not only that most of the variability is driven by the VDJ generation process, but there is a large degree of consistency between individuals with the inter-individual variance of repertoires being about ∼2% of the intra-individual variance. Known viral-specific TCRs follow the same generation and selection statistics as all TCRs.

Highlights

Most organisms live in a similar environment, facing common pathogenic threats
Using statistical models we learned the statistics of the processes generating this diversity from a large cohort of 651 individuals, including random generation and selection of T cells and their receptors
We developed a new computational tool SONIA that quantifies selection patterns in any sample of T cells by comparing statistics to background samples

Summary

Introduction

Most organisms live in a similar environment, facing common pathogenic threats. the adaptive immune system, based on the stochastic VDJ recombination process, is a naturally diverse system, supporting both repertoire variability within the individual, and variability across the population [1]. The adaptive immune system reacts against a variety of different threats to the organism This is achieved by maintaining a large ensemble of T cells, each having a different receptor that binds distinct subsets of antigens. The adaptive immune system maintains this diversity by generating a large repertoire of cells with different receptors [2,3,4] and selecting them according to their binding properties. Each human individual has 6 types of MHC molecules encoded by the very polymorphic human leukocyte antigen (HLA) locus All of these processes—receptor generation, selection, and peptide presentation—are stochastic in nature and depend on the host’s genetic background

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Results

Discussion

Conclusion