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

Harus Jabran Zahid^1*Damon May²Harlan Robins²Julia Greissl¹

• ¹Microsoft Research (United States), Redmond, United States
• ²Adaptive Biotechnologies Corporation, Seattle, United States

TCR diversity is essential for immune defense, yet the mechanisms underlying its decline with age 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 TCRβ diversity is almost entirely determined by repertoire size and the frequency of the 1,000 most abundant clones. These two measurable features of the repertoire explain 96% of the variance in TCRβ 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, which represent < 1% of TCRβ diversity, tracks a repertoire wide pattern of coordinated clonal expansion. Our findings indicate that this pattern is the 1 manifestation of a fundamental, previously unrecognized property of the immune system which we term intrinsic clonality. 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.