Early life imprints the hierarchy of T cell clone sizes

TL;DR

This study combines mathematical modeling and data analysis to show that early-life clonal expansions in T cells have a lasting impact on the immune repertoire, influencing clone size hierarchy throughout life.

Contribution

It introduces a quantitative model explaining how early clonal growth shapes the long-term T cell clone size hierarchy, supported by statistical analysis of sequencing data.

Findings

Early-life clonal expansions leave a lasting imprint on T cell repertoire.

The size hierarchy of T cell clones can be explained by clonal growth during repertoire formation.

Enrichment of early-founded clones persists over decades, affecting immune function.

Abstract

The adaptive immune system responds to pathogens by selecting clones of cells with specific receptors. While clonal selection in response to particular antigens has been studied in detail, it is unknown how a lifetime of exposures to many antigens collectively shape the immune repertoire. Here, through mathematical modeling and statistical analyses of T cell receptor sequencing data we demonstrate that clonal expansions during a perinatal time window leave a long-lasting imprint on the human T cell repertoire. We demonstrate how the empirical scaling law relating the rank of the largest clones to their size can emerge from clonal growth during repertoire formation. We statistically identify early founded clones and find that they are indeed highly enriched among the largest clones. This enrichment persists even after decades of human aging, in a way that is quantitatively predicted by a model of fluctuating clonal selection. Our work presents a quantitative theory of human T cell dynamics compatible with the statistical laws of repertoire organization and provides a mechanism for how early clonal dynamics imprint the hierarchy of T cell clone sizes with implications for pathogen defense and autoimmunity.