Quantifying changes in the T cell receptor repertoire during thymic development
- CNRS, France
- Weizmann Institute of Science, Israel
- University College London, United Kingdom
Abstract
One of the feats of adaptive immunity is its ability to recognize foreign pathogens while sparing the self. During maturation in the thymus, T cells are selected through the binding properties of their antigen-specific T-cell receptor (TCR), through the elimination of both weakly (positive selection) and strongly (negative selection) self-reactive receptors. However, the impact of thymic selection on the TCR repertoire is poorly understood. Here, we use transgenic Nur77-mice expressing a T-cell activation reporter to study the repertoires of thymic T cells at various stages of their development, including cells that do not pass selection. We combine high-throughput repertoire sequencing with statistical inference techniques to characterize the selection of the TCR in these distinct subsets. We find small but significant differences in the TCR repertoire parameters between the maturation stages, which recapitulate known differentiation pathways leading to the CD4+ and CD8+ subtypes. These differences can be simulated by simple models of selection acting linearly on the sequence features. We find no evidence of specific sequences or sequence motifs or features that are suppressed by negative selection. These results favour a collective or statistical model for T-cell self non-self discrimination, where negative selection biases the repertoire away from self recognition, rather than ensuring lack of self-reactivity at the single-cell level.
Data availability
All code for reproducing the figures of this paper can be found at https://github.com/statbiophys/ thymic_development_2022.git. The data has been deposited on the SRA as BioProject ID PRJNA804508 http://www.ncbi.nlm.nih.gov/bioproject/804508.
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thymic selection repertoires miceNCBI BioProject, PRJNA804508.
Article and author information
Author details
Aleksandra M Walczak
Funding
CNRS-Weizmann (80 prime)
- Francesco Camaglia
European Research Council (COG 724208)
- Aleksandra M Walczak
Agence Nationale de la Recherche (ANR-19-CE45-0018)
- Thierry Mora
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Frederik Graw, Heidelberg University, Germany
Ethics
Animal experimentation: The experiment was carried out using three 6-weeks old male inbred Nur77-GFP/Foxp3-mCherry (C57BL/6 background). The cross was bred and maintained at the Weizmann institute. All animals were handled according to Weizmann Institute's Animal Care guide- lines, in compliance with national and international regulations. This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols ({\#}21661115-2) of the Weizmann Institute of Science. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Weizmann Institute of Science. Every effort was made to minimize suffering.
Version history
- Preprint posted: February 15, 2022 (view preprint)
- Received: July 5, 2022
- Accepted: January 18, 2023
- Accepted Manuscript published: January 20, 2023 (version 1)
- Version of Record published: February 16, 2023 (version 2)
Copyright
© 2023, Camaglia et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Quantifying changes in the T cell receptor repertoire during thymic development
eLife 12:e81622.
https://doi.org/10.7554/eLife.81622
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