A computational approach to understanding the factors that shape the T cell receptor repertoire

Abstract

The shapes of the naive and memory T cell receptor (TCR) repertoires are key determinants of whether an effective immune response will be mounted in the face of infection; a careful balance of diversity and specificity is necessary in keeping infection under control. The factors that shape the repertoires are many and varied, and a thorough understanding of these factors is important as we seek to characterise healthy immune responses and develop efficacious vaccines. The generation of a diverse range of TCRs is enabled by a random gene recombination process in the thymus, but this process does not produce different TCRs with equal probability. Previous studies of antigen-specific T cell responses have shown that a process of convergent recombination – whereby multiple recombination events converge to produce the same nucleotide sequence, and multiple nucleotide sequences converge to produce the same amino acid sequence – leads to variable TCR production frequencies.

In this thesis, we have studied the role of these variable production frequencies in shaping the naive and memory TCRβ repertoires of CD8+ T cells. Millions of TCR sequences were obtained using traditional and high-throughput sequencing technologies, and analysed using novel computational methods. Higher frequency TCRβ clonotypes were more likely to be shared between individuals and present in both the naive and memory compartments. In turn, these higher-frequency clonotypes had the potential to be produced more efficiently during TCR gene recombination as demonstrated using computer simulations of a random recombination process. Furthermore, analysis of previously reported TCRα sequences from natural killer T cells and mucosal-associated invariant T cells in a variety of species showed that these ubiquitous receptors could also be efficiently made by the gene recombination process. This demonstrates that the effects of production efficiency are not limited to the TCRβ chain, nor are they limited to a particular species.

These findings highlight the important role that variable production efficiencies play in shaping the naive TCR repertoire, resulting in a contoured clonotypic landscape in the thymus. This landscape provides the basis for memory and virus-specific immune responses, and thus has implications for vaccine design and disease control.