Population Dynamics of Immune Repertoires

Desponds, Jonathan; Mayer, Andreas; Mora, Thierry; Walczak, Aleksandra M.

doi:10.1007/978-3-030-57204-4_12

Cited by 5 publications

(2 citation statements)

References 65 publications

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“…Furthermore, we only worked with data from flow-cytometry sorted non-antigen-experienced cells (pre-and naïve B cells). As hypothesized in the studies in the field (Marcou et al 2018;Sethna et al 2020;Desponds et al 2021), we argue that, although those cells have already undergone selection, the bias introduced by the selection is negligible when compared to the inter-individual differences: if selection impact on RGMP was too high, we would have seen that RGMP sets inferred from naïve B cell samples obtained from different subjects were indistinguishable (i.e., the distance would have been comparable to the distance caused by the noise). However, we see the opposite: although RGMP sets inferred from naïve B cell samples were closer to each other than RGMP sets inferred from pre-B cell samples, they were still clearly distinct (Fig.…”

Section: Methods 4 On the Strategy Not To Filter Unproductive Sequencesmentioning

confidence: 57%

Individualized VDJ recombination predisposes the available Ig sequence space

Slabodkin

Chernigovskaya

Mikocziova

et al. 2021

Preprint

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The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual's naive Ig repertoire, and consequently (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual-specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also non-genetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor-based individualized medicine approaches relevant to vaccination, infection, and autoimmunity.

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Section: Methods 4 On the Strategy Not To Filter Unproductive Sequencesmentioning

confidence: 57%

Individualized VDJ recombination predisposes the available Ig sequence space

Slabodkin

Chernigovskaya

Mikocziova

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Experimental evidence for large heterogeneity in division and survival rates within the naive T-cell pool has been shown in mice (Hogan et al, 2015;Rane et al, 2018;Reynaldi et al, 2019). Such experiments are not feasible in humans, but mathematical modelling has been used to assess how fitness differences between T-cell clones may affect the frequency of clones in the naive repertoire (Stirk et al, 2008(Stirk et al, , 2010Hapuarachchi et al, 2013;Lythe et al, 2016;Desponds et al, 2016Desponds et al, , 2021Dowling and Hodgkin, 2009;Johnson et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Chasing the chains by testing them twice

Greef¹

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The adaptive immune system employs a large number of T cells, that each have a specificity defined by their T-cell receptor (TCR). Characterizing the TCR repertoire in humans and mice thus provides a way to address outstanding immunological questions. The repertoires can be assessed quantitatively using high-throughput sequencing. Interpretation of the resulting data is challenging due to the vast diversity of the TCR repertoire and the relatively small number of cells that can be analyzed in an experiment. In this thesis we analyze TCR repertoires from humans and mice, by integrating information obtained from multiple samples. In Chapter 2 we devise various models for the distribution of TCR clone sizes in the human naive T cell pool. We characterise the repertoire of TCR α and β chains by repertoire sequencing of various cell subsets. Comparing the model predictions with the experimental outcomes, we find solid evidence for the presence of very large TCRαβ clones in the naive T cell repertoire. These large naive T-cell clones are only partly explained by their generation probability. Chapter 3 aims to identify sequence characteristics of such abundant naive T cell clones. We find that the D segment is missing in a substantial fraction of the abundant TCR β sequences in the naive T cell repertoire of young individuals. Such sequences appear to be mostly generated before birth, to persist over a human lifetime, and, as a result, to be excessively shared between individuals. Chapter 4 is a short unpublished report on quantifying the effects of age on the TCR repertoire. We present example analyses and discuss potential pitfalls of assessing ageing effects on the TCR repertoire. Chapter 5 describes a pilot study on using TCR sequencing to follow the T-cell response upon pneumococcal conjugate vaccination. We define quantitative requirements to classify T-cell expansions but detect these in only a minority of the donors. Our analysis suggests that the vaccine-induced T-cell response is small and/or very broad, and highlights experimental requirements to characterise such responses in future studies. A key limitation of the studies in humans introduced above is the limited number of cells that can be analysed compared to the total size of the T-cell pool. As a result, many of the TCR chains that make up the diversity of the TCR repertoire will be missed in any analysis. Bulk sequencing methods also do not uncover the full TCR diversity present in an individual as the information on the pairing of α and β chains is not obtained. In Chapter 6 we overcome both limitations by studying the TCR repertoire of one-TCRa mice that have a strongly reduced receptor diversity. This allows us to study the nearly complete TCR diversity, and compare the repertoire among individual lymph nodes and mice, revealing a spatial organisation of the TCR repertoire. In summary, this thesis describes how we studied T-cell biology quantitatively by combining simplified models with careful bioinformatics analyses.

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Individualized VDJ recombination predisposes the available Ig sequence space

et al. 2021

View full text Add to dashboard Cite

The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual's naive Ig repertoire and, consequently, (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also nongenetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor–based individualized medicine approaches relevant to vaccination, infection, and autoimmunity.

show abstract

Population Dynamics of Immune Repertoires

Cited by 5 publications

References 65 publications

Individualized VDJ recombination predisposes the available Ig sequence space

Individualized VDJ recombination predisposes the available Ig sequence space

Chasing the chains by testing them twice

Individualized VDJ recombination predisposes the available Ig sequence space

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