T cell receptor repertoires of mice and humans are clustered in similarity networks around conserved public CDR3 sequences

  1. Asaf Madi
  2. Asaf Poran
  3. Eric Shifrut
  4. Shlomit Reich-Zeliger
  5. Erez Greenstein
  6. Irena Zaretsky
  7. Tomer Arnon
  8. Francois Van Laethem
  9. Alfred Singer
  10. Jinghua Lu
  11. Peter D Sun
  12. Irun R Cohen
  13. Nir Friedman  Is a corresponding author
  1. Weizmann Institute of Science, Israel
  2. Weizmann Institute, Israel
  3. National Cancer Institute, United States
  4. National Institute of Allergy and Infectious Diseases, United States

Abstract

Diversity of T cell receptor (TCR) repertoires, generated by somatic DNA rearrangements, is central to immune system function. However, the level of sequence similarity of TCR repertoires within and between species has not been characterized. Using network analysis of high-throughput TCR sequencing data, we found that abundant CDR3-TCRβ sequences were clustered within networks generated by sequence similarity. We discovered a substantial number of public CDR3-TCRβ segments that were identical in mice and humans. These conserved public sequences were central within TCR sequence-similarity networks. Annotated TCR sequences, previously associated with self-specificities such as autoimmunity and cancer, were linked to network clusters. Mechanistically, CDR3 networks were promoted by MHC-mediated selection, and were reduced following immunization, immune checkpoint blockade or aging. Our findings provide a new view of T cell repertoire organization and physiology, and suggest that the immune system distributes its TCR sequences unevenly, attending to specific foci of reactivity.

Data availability

The following previously published data sets were used
    1. Nir Friedman
    (2015) Young mice TCR repertoire
    Publicly available at NCBI Sequence Read Archive (accession no: SRP042610).

Article and author information

Author details

  1. Asaf Madi

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3441-3228
  2. Asaf Poran

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Eric Shifrut

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Shlomit Reich-Zeliger

    Department of Immunology, Weizmann Institute, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Erez Greenstein

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Irena Zaretsky

    Department of Immunology, Weizmann Institute, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4161-4677
  7. Tomer Arnon

    Department of Immunology, Weizmann Institute, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Francois Van Laethem

    Experimental Immunology Branch, National Cancer Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Alfred Singer

    Experimental Immunology Branch, National Cancer Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jinghua Lu

    Structural Immunology Section, National Institute of Allergy and Infectious Diseases, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Peter D Sun

    Structural Immunology Section, National Institute of Allergy and Infectious Diseases, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Irun R Cohen

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  13. Nir Friedman

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    For correspondence
    nir.friedman@weizmann.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9678-3550

Funding

Minerva Foundation

  • Nir Friedman

Federal German Ministry for Education and Research

  • Nir Friedman

I-CORE

  • Nir Friedman

Israel Science Foundation

  • Nir Friedman

M.D. Moross Institute for Cancer Reseach

  • Asaf Madi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: 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 (#24110116-2) 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. Arup K Chakraborty, Ragon Institute of MGH, MIT and Harvard, United States

Publication history

  1. Received: October 10, 2016
  2. Accepted: July 14, 2017
  3. Accepted Manuscript published: July 21, 2017 (version 1)
  4. Version of Record published: August 11, 2017 (version 2)

Copyright

© 2017, Madi 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. Asaf Madi
  2. Asaf Poran
  3. Eric Shifrut
  4. Shlomit Reich-Zeliger
  5. Erez Greenstein
  6. Irena Zaretsky
  7. Tomer Arnon
  8. Francois Van Laethem
  9. Alfred Singer
  10. Jinghua Lu
  11. Peter D Sun
  12. Irun R Cohen
  13. Nir Friedman
(2017)
T cell receptor repertoires of mice and humans are clustered in similarity networks around conserved public CDR3 sequences
eLife 6:e22057.
https://doi.org/10.7554/eLife.22057

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