Insights into immune system development and function from mouse T-cell repertoires

Abstract

The ability of the adaptive immune system to respond to arbitrary pathogens stems from the broad diversity of immune cell surface receptors. This diversity originates in a stochastic DNA editing process (VDJ recombination) that acts on the surface receptor gene each time a new immune cell is created from a stem cell. By analyzing T-cell receptor (TCR) sequence repertoires taken from the blood and thymus of mice of different ages, we quantify the changes in the VDJ recombination process that occur from embryo to young adult. We find a rapid increase with age in the number of random insertions and a dramatic increase in diversity. Because the blood accumulates thymic output over time, blood repertoires are mixtures of different statistical recombination processes, and we unravel the mixture statistics to obtain a picture of the time evolution of the early immune system. Sequence repertoire analysis also allows us to detect the statistical impact of selection on the output of the VDJ recombination process. The effects we find are nearly identical between thymus and blood, suggesting that our analysis mainly detects selection for proper folding of the TCR receptor protein. We further find that selection is weaker in laboratory mice than in humans and it does not affect the diversity of the repertoire.

Predicting the spectrum of TCR repertoire sharing with a data‐driven model of recombination

“…We find that the distribution of generation probabilities of all TCRβ CDR3 amino acid sequences (Figure 5, blue curves) is extremely broad, spanning many orders of magnitude. This observation is consistent with similar analyses at the level of nucleotide sequences in non‐productive26 and productive20 human TCRβ, in the α and β chains of monozygous twins,22 and mice 28. If we plot instead the generative probability distribution of sequences that are shared among two or more individuals in our dataset, we find that the distribution narrows and shifts toward higher generation probabilities20, 22, 26 as expected.…”

“…Due to their publicness, it had been conjectured that some of these common TCRs might have a close to innate function 31. In this context, it should be noted that young, prebirth repertoires are known to be much less diverse both in humans22 and mice,28 due the late appearance of TdT, the enzyme responsible for insertions in the recombination process. Consequently, the prebirth repertoire is expected to be much more public that the adult one, and could be enriched in innate‐like TCRs.…”

The Bayesian optimist's guide to adaptive immune receptor repertoire analysis

“…The distribution of inserted sequences invites further exploration: are more complex models warranted? Although current models are inferred per-data-set, it would be helpful to have models that can concern multiple related data sets and parameterize differences between them using covariates such as age (61). Such models may also be useful to infer differences in the rearrangement process by genetic background (41, 46, 70).…”

The expanding role of systems immunology in decoding the T cell receptor repertoire

“…It is also expected that future attentions will become more focused towards the development of computational and statistical methods that are more closely integrated with the experimental design of TCR sequencing strategies to facilitate specific interrogation of TCR repertoires, as well as experimental approaches that target specific mechanisms impacting TCR repertoires. For example, current models of TCR recombination are largely based on mechanistically-simplified single-stranded DNA models and infer recombination probabilities based on pre- and post-selection repertoire sequencing data [9,10,33]. While these models have provided valuable insights, there is still scope to improve our understanding of the gene recombination process and thus improve recombination models.…”

“…Recent research is making progress in each of these directions towards resolving the TCR repertoire system, with substantial contributions from computational analysis of data and/or computational and mathematical modeling (Figure 1). Continuing with the example above, the goal of understanding the composition of the peripheral TCR repertoire is being pursued through studies of the specific processes of gene recombination mechanisms [33,39-42], thymic selection [43-48] and the mechanisms regulating the peripheral repertoire [49-53]. In parallel, broader-focus investigations are considering both the interactions between these processes in shaping the peripheral TCR repertoire [41,43,54] and the organizational structure of the peripheral TCR repertoire [37,55-57].…”