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A conserved structural organization of the human public TCRβ repertoire persists throughout exceptional longevity

Preprint: cohort study in peopleAI & data
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Abstract

The human public T-cell receptor (TCR) repertoire provides a shared immunological framework across individuals, yet whether it possesses a conserved higher-order structural organization and how this organization is affected by lifelong immune ageing remain unknown. Here, we constructed a structural atlas of the human public TCRβ repertoire from 1.33 million unique public CDR3β sequences derived from healthy Adults (<70 years) and Elders (>80 years). The atlas comprised 64 reproducible Structural Sequence Modules (SSMs) representing sequence-coherent neighborhoods supported by quantitative model selection and independent topological validation. Projection of individual repertoires onto this common framework demonstrated complete preservation of all SSMs across both cohorts. Although 18 modules exhibited significant differences in unweighted occupancy, the global module hierarchy remained highly conserved, indicating that exceptional longevity is associated primarily with quantitative redistribution among pre-existing structural compartments rather than loss or replacement of repertoire organization. Rarefaction analysis demonstrated that unequal cohort size strongly influenced public-clonotype discovery but had minimal impact on the direction and magnitude of module-level occupancy differences, whereas frequency-weighted analysis indicated that remodeling was not primarily driven by expansion of highly abundant public clonotypes. Susceptibility to remodeling was associated mainly with module size and within-module CDR3β length variability. Module publicness was highly conserved across age groups and associated with coordinated sequence, germline and network properties, while TRBJ usage was substantially more strongly associated with SSM identity than TRBV usage. Finally, curated antigen annotations were non-randomly distributed across SSMs, demonstrating module-level functional biases, although structural proximity did not generally predict similarity in antigen-recognition profiles. Together, these findings identify higher-order structural organization as a robust property of the human public TCRβ repertoire. Exceptional longevity preserves this organization while selectively remodeling the occupancy of pre-existing Structural Sequence Modules, distinguishing age-associated quantitative redistribution from cohort-size effects and clonal expansion. The structural atlas therefore provides a reproducible framework for investigating the organization and remodeling of adaptive immune repertoires across ageing and immune-mediated conditions.