Peter C. de Greef

Utrecht University

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Rob J. de Boer

Utrecht University

Rutger Hermsen

Utrecht University

Mazlina Ismail

University College London

James Heather

Weatherford College

Benny Chain

University College London

Bram Gerritsen

Yale University

Theres Oakes

University College London

José A. M. Borghans

University Medical Center Utrecht

Marion Hendriks

National Institute for Public Health and the Environment

Josien Lanfermeijer

National Institute for Public Health and the Environment

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Utrecht University

National Institute for Public Health and the Environment

University Medical Center Utrecht

University College London

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Institute of Infection and Immunity

Paul Ehrlich Institut

St George's, University of London

Oxford BioMedica (United Kingdom)

Centre National de la Recherche Scientifique

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Author response: The naive T-cell receptor repertoire has an extremely broad distribution of clone sizes

Peter C. de Greef Theres Oakes Bram Gerritsen Mazlina Ismail James Heather

clone (Java method)

10.7554/elife.49900.sa2

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On the feasibility of using TCR sequencing to follow a vaccination response – lessons learned

Frontiers in Immunology (2023)

Peter C. de Greef Josien Lanfermeijer Marion Hendriks Alper Çevirgel Martijn Vos

T cells recognize pathogens by their highly specific T-cell receptor (TCR), which can bind small fragments of an antigen presented on the Major Histocompatibility Complex (MHC). Antigens that are provided through vaccination cause specific T cells to respond by expanding and forming specific memory to combat a future infection. Quantification of this T-cell response could improve vaccine monitoring or identify individuals with a reduced ability to respond to a vaccination. In this proof-of-concept study we use longitudinal sequencing of the TCRβ repertoire to quantify the response in the CD4+ memory T-cell pool upon pneumococcal conjugate vaccination. This comes with several challenges owing to the enormous size and diversity of the T-cell pool, the limited frequency of vaccine-specific TCRs in the total repertoire, and the variation in sample size and quality. We defined quantitative requirements to classify T-cell expansions and identified critical parameters that aid in reliable analysis of the data. In the context of pneumococcal conjugate vaccination, we were able to detect robust T-cell expansions in a minority of the donors, which suggests that the T-cell response against the conjugate in the pneumococcal vaccine is small and/or very broad. These results indicate that there is still a long way to go before TCR sequencing can be reliably used as a personal biomarker for vaccine-induced protection. Nevertheless, this study highlights the importance of having multiple samples containing sufficient T-cell numbers, which will support future studies that characterize T-cell responses using longitudinal TCR sequencing.

Pneumococcal Conjugate Vaccine

10.3389/fimmu.2023.1210168

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Age and CMV-Infection Jointly Affect the EBV-Specific CD8+ T-Cell Repertoire

Frontiers in Aging (2021)

Josien Lanfermeijer Peter C. de Greef Marion Hendriks Martijn Vos Josine van Beek

CD8

Memory T cell

10.3389/fragi.2021.665637

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The TCR assigns naive T cells to a preferred lymph node

Science Advances (2024)

Peter C. de Greef Sospeter Ngoci Njeru Claudia Benz Simon Fillatreau Bernard Malissen

Naive T cells recirculate between the spleen and lymph nodes where they mount immune responses when meeting dendritic cells presenting foreign antigen. As this may happen anywhere, naive T cells ought to visit all lymph nodes. Here, deep sequencing almost-complete TCR repertoires led to a comparison of different lymph nodes within and between individual mice. We find strong evidence for a deterministic CD4/CD8 lineage choice and a consistent spatial structure. Specifically, some T cells show a preference for one or multiple lymph nodes, suggesting that their TCR interacts with locally presented (self-)peptides. These findings are mirrored in TCR-transgenic mice showing localized CD69 expression, retention, and cell division. Thus, naive T cells intermittently sense antigenically dissimilar niches, which is expected to affect their homeostatic competition.

10.1126/sciadv.adl0796

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TCRβrearrangements without D-segment are common, abundant and public

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Peter C. de Greef Rob J. de Boer

Abstract T cells play an important role in adaptive immunity. An enormous clonal diversity of T-cells with a different specificity, encoded by the T-cell receptor (TCR), protect the body against infection. Most TCR β chains are generated from a V-, D-, and J-segment during recombination in the thymus. Although complete absence of the D-segment is not easily detectable from sequencing data, we find convincing evidence for a substantial proportion of TCR β rearrangements lacking a D-segment. Additionally, sequences without a D-segment are more likely to be abundant within individuals and/or shared between individuals. We find that such sequences are preferentially generated during fetal development and persist within the elderly. Summarizing, TCR β rearrangements without a D-segment are not uncommon, and tend to allow for TCR β chains with a high abundance in the naive repertoire.

10.1101/2021.03.05.434088

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TCRβ rearrangements without a D segment are common, abundant, and public

Proceedings of the National Academy of Sciences (2021)

Peter C. de Greef Rob J. de Boer

Significance The human body detects foreign pathogens by T cells with specific receptors. These are not directly encoded in the genome but generated in a random process that combines small gene segments into functional subunits of the receptor. The β -chain of the T cell receptor is normally composed of three such gene segments. Here we identify a group of T cells that lack the middle segment in their receptor sequence. We find that such sequences are mostly generated before birth, persist over a human lifetime, and, as a result, are excessively shared between individuals.

10.1073/pnas.2104367118

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Towards a robust comparison of diversity between sampled TCR repertoires

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Peter C. de Greef Rob J. de Boer

Abstract T-cell receptor (TCR) repertoire sequencing data provides quantitative insight into the distribution of T-cell clones. The diversity of the TCR repertoire in humans tends do decrease with age, which may be a key determinant explaining immune senescence in older individuals. To address this, we first analyze how the diversity of a potential T-cell response against an unseen pathogen changes with age. Next, we discuss the complications with interpreting the outcomes of such an analysis. Specifically, the changes in T-cell subset sizes confound analyses of TCR diversity, and typical sample sizes do not easily allow for a robust quantification of this diversity. Thus, explaining immune senescence as a result of decreasing TCR diversity is far from straightforward and requires a detailed, robust, and quantitative analysis.

Senescence

10.1101/2023.02.10.528010

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The naive T-cell receptor repertoire has an extremely broad distribution of clone sizes

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Peter C. de Greef Theres Oakes Bram Gerritsen Mazlina Ismail James Heather

Abstract The human naive T-cell receptor (TCR) repertoire is extremely diverse and accurately estimating its distribution is challenging. We address this challenge by combining a quantitative sequencing protocol of TCRA and TCRB sequences with computational modelling. We observed the vast majority of TCR chains only once in our samples, confirming the enormous diversity of the naive repertoire. However, a substantial number of sequences were observed multiple times within samples, and we demonstrated that this is due to expression by many cells in the naive pool. We reason that α and β chains are frequently observed due to a combination of selective processes and summation over multiple clones expressing these chains. We test the contribution of both mechanisms by predicting samples from phenomenological and mechanistically modelled repertoire distributions. By comparing these with sequencing data, we show that frequently observed chains are likely to be derived from multiple clones. Still, a neutral model of T-cell homeostasis cannot account for the observed distributions. We conclude that the data are only compatible with distributions of many small clones in combination with a sufficient number of very large naive T-cell clones, the latter most likely as a result of peripheral selection.

clone (Java method)

10.1101/691501

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The naive T-cell receptor repertoire has an extremely broad distribution of clone sizes

eLife (2020)

Peter C. de Greef Theres Oakes Bram Gerritsen Mazlina Ismail James Heather

The clone size distribution of the human naive T-cell receptor (TCR) repertoire is an important determinant of adaptive immunity. We estimated the abundance of TCR sequences in samples of naive T cells from blood using an accurate quantitative sequencing protocol. We observe most TCR sequences only once, consistent with the enormous diversity of the repertoire. However, a substantial number of sequences were observed multiple times. We detect abundant TCR sequences even after exclusion of methodological confounders such as sort contamination, and multiple mRNA sampling from the same cell. By combining experimental data with predictions from models we describe two mechanisms contributing to TCR sequence abundance. TCRα abundant sequences can be primarily attributed to many identical recombination events in different cells, while abundant TCRβ sequences are primarily derived from large clones, which make up a small percentage of the naive repertoire, and could be established early in the development of the T-cell repertoire.

clone (Java method)

10.7554/elife.49900

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Citations (82)