Precise tracking of vaccine-responding T-cell clones reveals convergent and personalized response in identical twins

Pogorelyy, Mikhail V.; Minervina, Anastasia A.; Touzel, Maximilian Puelma; Sycheva, Anastasiia L.; Komech, Ekaterina A.; Kovalenko, Elena I.; Karganova, Galina G.; Egorov, Evgeniy S.; Komkov, Alexander; Chudakov, Dmitriy M.; Mamedov, Ilgar Z.; Mora, Thierry; Walczak, Aleksandra M.; Lebedev, Yuri B

doi:10.1101/300343

Cited by 14 publications

(16 citation statements)

References 37 publications

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“…Specifically, the recruitment of novel vaccine-specific T-cell clonotypes into memory compartment following vaccination can be tracked by examining the CD4 memory TCRβ repertoire over time. While we observed no increase in the frequency of the vaccine-specific memory T-cells, as the time point may have missed the peak of the clonal expansion of effector CD4 T cells as was reported before (Blom et al, 2013; Kohler et al, 2012; Pogorelyy et al, 2018), a significant rise in the number of unique vaccine-specific T-cell clonotypes was detected. This observation is consistent with earlier studies of T cell immune repertoire that showed that antigen-specific TCRβ sequences do not always overlap with those sequences that increase in frequency after infection or vaccination (DeWitt et al, 2015).…”

Section: Discussionsupporting

confidence: 48%

Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon hepatitis B vaccination

Meysman

Bartholomeus

Neuter

et al. 2020

Preprint

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Antigen recognition through the T cell receptor (TCR) αβ heterodimer is one of the primary determinants of the adaptive immune response. Vaccines activate naïve T cells with high specificity to expand and differentiate into memory T cells that allow for a quick and robust T cell response upon exposure to the pathogen or re-exposure to the vaccine antigen. This is why the induction of memory T cells is a key feature in vaccine development. However, it has become increasingly evident that antigen-specific memory CD4 and CD8 T cells exist in unexposed antigen-naïve hosts and it is likely that exposure to one antigen might alter the TCR repertoire of memory T cells to a different unrelated antigen. In this study, we utilize high-throughput sequencing to profile the memory CD4 TCRβ repertoire and track vaccine-specific TCRβ clonotypes following the de novo administration of hepatitis B (HepB) vaccine in healthy HepB-naïve individuals and show that vaccinees with preexisting vaccine-specific memory CD4 T cell clonotypes elicited earlier and higher antibody concentrations and mounted a more robust CD4 T cell response to the vaccine. We further identify vaccine-specific TCRβ sequence patterns that can be used to predict which individuals will have an early and more vigorous vaccine-elicited immunity to HepB vaccine. Moreover, we find that an expansion of 4-1BB+ memory TREG is a prominent feature in individuals with delayed and modest vaccine-induced immunity. Our approach shows that modeling pre-vaccination TCRβ repertoire enables prediction of both antibody and CD4 responses to vaccines.

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Section: Discussionsupporting

confidence: 48%

Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon hepatitis B vaccination

Meysman

Bartholomeus

Neuter

et al. 2020

Preprint

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“…A clonotype expansion of 10 4 (not unexpected in the context of an immune response, see e.g. [ 35 ]) would be sufficient to explain this result.…”

Section: Discussionmentioning

confidence: 76%

Genesis of the αβ T-cell receptor

et al. 2019

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The T-cell (TCR) repertoire relies on the diversity of receptors composed of two chains, called α and β, to recognize pathogens. Using results of high throughput sequencing and computational chain-pairing experiments of human TCR repertoires, we quantitively characterize the αβ generation process. We estimate the probabilities of a rescue recombination of the β chain on the second chromosome upon failure or success on the first chromosome. Unlike β chains, α chains recombine simultaneously on both chromosomes, resulting in correlated statistics of the two genes which we predict using a mechanistic model. We find that ∼35% of cells express both α chains. Altogether, our statistical analysis gives a complete quantitative mechanistic picture that results in the observed correlations in the generative process. We learn that the probability to generate any TCRαβ is lower than 10−12 and estimate the generation diversity and sharing properties of the αβ TCR repertoire.

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“…Probability estimates from these models can be used to draw important biological conclusions. For example, observing sequences that are amplified in a repertoire indicates that they perform important functions like targeting yellow fewer or cytomegalovirus (Pogorelyy et al, 2018c; Pogorelyy et al, 2018d; Emerson et al, 2017). However, in order to properly define amplification, we must infer the frequency of such sequences appearing in the naive (i.e.…”

Section: Introductionmentioning

confidence: 99%

Deep generative models for T cell receptor protein sequences

Davidsen

Olson

DeWitt

et al. 2019

eLife

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Probabilistic models of adaptive immune repertoire sequence distributions can be used to infer the expansion of immune cells in response to stimulus, differentiate genetic from environmental factors that determine repertoire sharing, and evaluate the suitability of various target immune sequences for stimulation via vaccination. Classically, these models are defined in terms of a probabilistic V(D)J recombination model which is sometimes combined with a selection model. In this paper we take a different approach, fitting variational autoencoder (VAE) models parameterized by deep neural networks to T cell receptor (TCR) repertoires. We show that simple VAE models can perform accurate cohort frequency estimation, learn the rules of VDJ recombination, and generalize well to unseen sequences. Further, we demonstrate that VAE-like models can distinguish between real sequences and sequences generated according to a recombination-selection model, and that many characteristics of VAE-generated sequences are similar to those of real sequences.

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Precise tracking of vaccine-responding T-cell clones reveals convergent and personalized response in identical twins

Cited by 14 publications

References 37 publications

Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon hepatitis B vaccination

Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon hepatitis B vaccination

Genesis of the αβ T-cell receptor

Deep generative models for T cell receptor protein sequences

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