There are only an estimated 10 13 cells in the human body, and many clonotypes are of high abundance due to strong selection forces (for example, thymic education or antigen specificity). However, the actual diversity of a person's TCR repertoire cannot possibly lie in this range. By recombination, random insertion, deletion and substitution, the small set of genes that encode the T-cell receptor has the potential to create between 10 15 and 10 20 TCR clonotypes (a clonotype is a population of T cells that carry an identical TCR). The human T-cell receptor (TCR) repertoire-the range of different TCRs expressed-plays a vital role in host defence. We highlight our recently developed estimator, DivE, which can accurately estimate diversity across a range of immunological and biological systems. We show that existing approaches have significant shortcomings, and frequently underestimate true TCR diversity. We review the diversity (species richness) estimators that have been applied to T-cell repertoires and the methods used to validate these estimators. This is analogous to the ‘unseen species problem’ in ecology. Consequently, estimators of the total number of TCR clonotypes that are present in the individual, in addition to those observed, are essential. The diversity is high and the frequency distribution of individual TCRs is heavily skewed the diversity therefore cannot be captured in a blood sample. However, direct measurement of total TCR diversity is impossible. A highly diverse T-cell receptor (TCR) repertoire is a fundamental property of an effective immune system, and is associated with efficient control of viral infections and other pathogens.
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