The many important facets of T-cell repertoire diversity

Key Points Intense investigation has elucidated the molecular mechanisms that generate the structural diversity of the T-cell receptor (TCR) repertoire. The first reliable estimates of actual TCR diversity were recently published, however, the biological impact of TCR diversity is still being investigated. Potential TCR diversity, which is in the order of 1 × 10 15 before thymic selection, and 1 × 10 13 after thymic selection, stands in sharp contrast with the estimated actual, expressed diversity in a given organism at a given time point — 2 × 10 6 in mice and 2 × 10 7 in humans. This limit is imposed in part by the fact that there are fewer T cells in the body than there are potential TCR molecules. However, the potential of ∼1 × 10 13 TCRs is used, but in different organisms over time. It was shown that even genetically identical animals express highly diverse TCR repertoires, with as little as 20% overlap between them. Structural TCR diversity is broadened by TCR crossreactivity — the propensity of a TCR to react with more than one peptide–MHC (pMHC) ligand. However, sharp differences exist in our estimates of TCR crossreactivity (some authors estimate that a single TCR might recognize more than 1 × 10 6 pMHC ligands) and in the threshold at which this crossreactivity becomes important in pathogen resistance. T cells also show functional diversification (that is, the ability to mobilize distinct effector and regulatory functions) and this diversity is probably important for combating pathogens. T-cell diversity contributes to immune defence in two ways: it provides an initial pool from which the best and most efficient T cells will be selected to attack the pathogen; and it provides the flexible TCR reserve should the pathogen attempt to escape by mutation. Evidence from models with experimental or spontaneous restrictions in TCR diversity shows that in most models, even modest reductions in structural diversity tend to result in impaired responses to antigens and pathogens. This indicates that in most cases, TCR crossreactivity cannot compensate for the loss of structural diversity, indicating that the biological relevance of TCR crossreactivity for pathogen resistance is rather limited. There is a natural reduction in TCR diversity on aging and a pathophysiological reduction in TCR diversity after infection with HIV/highly active antiretroviral therapy and after bone-marrow transplantation. These conditions represent outstanding (and clinically relev