Genesis of the alpha beta T-cell receptor

TL;DR

This paper provides a detailed quantitative analysis of the human T-cell receptor alpha-beta generation process, revealing probabilities, correlations, and diversity metrics through high-throughput sequencing and mechanistic modeling.

Contribution

It introduces a mechanistic model for TCR alpha-beta recombination, estimating probabilities and correlations, and characterizes the diversity and sharing properties of the TCR repertoire.

Findings

Approximately 28% of cells express both alpha chains.

Shared beta chains with different alpha chains are overrepresented.

The probability of generating any TCR alpha-beta pair is less than 10^-12.

Abstract

The T-cell (TCR) repertoire relies on the diversity of receptors composed of two chains, called $\alpha$ and $\beta$, to recognize pathogens. Using results of high throughput sequencing and computational chain-pairing experiments of human TCR repertoires, we quantitively characterize the $\alpha\beta$ generation process. We estimate the probabilities of a rescue recombination of the $\beta$ chain on the second chromosome upon failure or success on the first chromosome. Unlike $\beta$ chains, $\alpha$ chains recombine simultaneously on both chromosomes, resulting in correlated statistics of the two genes which we predict using a mechanistic model. We find that $\sim 28 \%$ of cells express both $\alpha$ chains. We report that clones sharing the same $\beta$ chain but different $\alpha$ chains are overrepresented, suggesting that they respond to common immune challenges. Altogether, our statistical analysis gives a complete quantitative mechanistic picture that results in the observed correlations in the generative process. We learn that the probability to generate any TCR$\alpha\beta$ is lower than $10^{-12}$ and estimate the generation diversity and sharing properties of the $\alpha\beta$ TCR repertoire.