Quantifying changes in the T cell receptor repertoire during thymic development

  1. Francesco Camaglia
  2. Arie Ryvkin
  3. Erez Greenstein
  4. Shlomit Reich-Zeliger
  5. Benny Chain
  6. Thierry Mora  Is a corresponding author
  7. Aleksandra M Walczak  Is a corresponding author
  8. Nir Friedman
  1. CNRS, France
  2. Weizmann Institute of Science, Israel
  3. 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.

The following data sets were generated

Article and author information

Author details

  1. Francesco Camaglia

    Laboratoire de physique de l'École normale supérieure, CNRS, Paris, France
    Competing interests
    No competing interests declared.
  2. Arie Ryvkin

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  3. Erez Greenstein

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6923-8469
  4. Shlomit Reich-Zeliger

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  5. Benny Chain

    Division of Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7417-3970
  6. Thierry Mora

    Laboratoire de physique de l'École normale supérieure, CNRS, Paris, France
    For correspondence
    thierry.mora@phys.ens.fr
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5456-9361
  7. Aleksandra M Walczak

    Laboratoire de physique de l'École normale supérieure, CNRS, Paris, France
    For correspondence
    aleksandra.walczak@phys.ens.fr
    Competing interests
    Aleksandra M Walczak, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2686-5702
  8. Nir Friedman

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.

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.

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.

Reviewing Editor

  1. Frederik Graw, Heidelberg University, Germany

Publication history

  1. Received: July 5, 2022
  2. Accepted: January 18, 2023
  3. Accepted Manuscript published: January 20, 2023 (version 1)

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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  1. Francesco Camaglia
  2. Arie Ryvkin
  3. Erez Greenstein
  4. Shlomit Reich-Zeliger
  5. Benny Chain
  6. Thierry Mora
  7. Aleksandra M Walczak
  8. Nir Friedman
(2023)
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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