Mouse T cell repertoires as statistical ensembles: overall characterization and age dependence

TL;DR

This study analyzes mouse T cell receptor repertoires across different ages, revealing how diversity increases with age due to changes in VDJ recombination and how selection influences the repertoire, providing insights into immune system development.

Contribution

It offers a detailed statistical characterization of T cell receptor diversity and its evolution with age, highlighting the impact of VDJ recombination and selection processes.

Findings

Diversity increases rapidly with age due to more insertions in VDJ recombination.

Blood repertoires reflect a mixture of recombination processes over time.

Selection effects are similar in thymus and blood, indicating structural constraints.

Abstract

The ability of the adaptive immune system to respond to arbitrary pathogens stems from the broad diversity of immune cell surface receptors (TCRs). This diversity originates in a stochastic DNA editing process (VDJ recombination) that acts each time a new immune cell is created from a stem cell. By analyzing T cell sequence repertoires taken from the blood and thymus of mice of different ages, we quantify the significant changes in this process that occur in development from embryo to young adult. We find a rapid increase with age in the number of random insertions in the VDJ recombination process, leading to a dramatic increase in diversity. Since the blood accumulates thymic output over time, blood repertoires are mixtures of different statistical recombination processes and, by unraveling the mixture statistics, we can obtain a clear picture of the time evolution of the early immune system. Sequence repertoire analysis also allows us to detect the effect of selection on the output of the VDJ recombination process. The effects we find are nearly identical between thymus and blood, suggesting that they mainly reflect selection for proper folding of the TCR receptor protein.