A Fundamental Relationship between TCR Diversity, Repertoire Size and Systemic Clonal Expansion: Insights from 30,000 TCRβ Repertoires

Abstract TCR diversity is essential for immune defense, yet the mechanisms underlying its decline with age, its dependence on sex and its variation among individuals remain poorly understood. These patterns are often attributed to passive loss from factors such as thymic atrophy and cumulative immune exposures but such processes fail to explain the systematic variation observed across populations. Here we challenge this view by analyzing TCRβ repertoires from ∼30, 000 individuals showing that TCR diversity is almost entirely determined by repertoire size and the frequency of the 1,000 most abundant clones. These two intrinsic features of the repertoire explain 96% of the variance in TCR diversity, capturing its dependence on age and sex and defining a robust relationship that holds even under strong immune perturbations such as Cytomegalovirus infection. This relationship arises because the frequency of abundant clones captures a repertoire-wide pattern of coordinated clonal expansion—termed intrinsic clonality—which may be a fundamental, previously unrecognized property of the immune system. We propose that TCR diversity emerges as a system-level property mediated by repertoire size and intrinsic clonality, both of which are likely homeostatically regulated. These findings offer a new conceptual framework for understanding TCR diversity within immune homeostasis which may guide therapies aimed at restoring immune function. Competing Interest Statement HJ Zahid, J Greissl have employment and equity ownership with Microsoft. D May, HS Robins have employment and equity ownership with Adaptive Biotechnologies. The authors declare no other competing interests. Footnotes Updated data availability statement and Discussion section.