Diversity, Equality, and Inclusion in the naïve T Cell Receptor Repertoire

Abstract

The naïve T cell receptor (TCR) repertoire forms the immunological background from which adaptive cellular immune responses emerge. We examine the fundamental properties of the human naïve TCR repertoire through the perspective of Diversity, Equality, and Inclusion. We first consider the richness of the repertoire. A combination of experimental and computational approaches has been used to estimate that the human repertoire contains at least 100 million distinct naïve clonotypes. This estimate suggests an average size of each clonotype of 1000 T cells. However, evidence from both mathematical modeling and large-scale single-cell sequencing indicates that clonotype family sizes are very unequal, with a small subset of naïve TCRs present at substantially higher frequencies. Somatic recombination itself does not contribute significantly to this inequality, as the probability of generating an identical clonotype multiple times in an individual is very small. Instead, clonotype size is likely to be largely driven by thymic or post-thymic expansion, but the mechanisms driving heterogeneity remain poorly understood. Finally, despite clonal deletion being a cornerstone of immunological dogma, experimental evidence for functional “holes” in the naïve repertoire caused by negative thymic selection is surprisingly limited. Alternative tolerance mechanisms, including regulatory T cells and T cell quorum sensing, are likely to play important roles. This review highlights the need for further research to identify the mechanisms that shape the frequency distribution of naïve TCR clone sizes and to define its impact on primary immune responses. Further research is also needed to understand the role of quorum sensing in maintaining T cell tolerance, while avoiding potential vulnerabilities arising from extensive ‘holes’ in the TCR repertoire.