1. Developmental Biology
  2. Immunology and Inflammation

T cell self-reactivity during thymic development dictates the timing of positive selection

  1. Lydia K Lutes
  2. Zoë Steier
  3. Laura L McIntyre
  4. Shraddha Pandey
  5. James Kaminski
  6. Ashley R Hoover
  7. Silvia Ariotti
  8. Aaron Streets
  9. Nir Yosef
  10. Ellen A Robey  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Boston Children's Hospital, United States
  3. University of Lisbon, Portugal
https://doi.org/10.7554/eLife.65435
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Cite this article
  1. Lydia K Lutes
  2. Zoë Steier
  3. Laura L McIntyre
  4. Shraddha Pandey
  5. James Kaminski
  6. Ashley R Hoover
  7. Silvia Ariotti
  8. Aaron Streets
  9. Nir Yosef
  10. Ellen A Robey
(2021)
T cell self-reactivity during thymic development dictates the timing of positive selection
eLife 10:e65435.
https://doi.org/10.7554/eLife.65435
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  3. Download .RIS

Abstract

Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced TCR sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity down-regulate TCR sensitivity more slowly during positive selection, and associate membrane ion channel expression with thymocyte self-reactivity and progress through positive selection.

Data availability

RNA-seq data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE164896.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Lydia K Lutes

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Zoë Steier

    Department of Bioengineering, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Laura L McIntyre

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Shraddha Pandey

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. James Kaminski

    Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Ashley R Hoover

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Silvia Ariotti

    Instituto de Medicina Molecular João Lobo Antunes, University of Lisbon, Lisbon, Portugal
    Competing interests
    The authors declare that no competing interests exist.

  8. Aaron Streets

    Department of Bioengineering, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Nir Yosef

    Department of Electrical Engineering and Computer Science and the Center for Computational Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9004-1225

  10. Ellen A Robey

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    erobey@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3630-5266

Funding

National Institutes of Health (RO1AI064227)

  • Ellen A Robey

National Institutes of Health (T32AI100829)

  • Laura L McIntyre
  • Ashley R Hoover

Human Frontiers Fellowship

  • Silvia Ariotti

National Science Foundation (GRFP)

  • Zoë Steier

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

Reviewing Editor

  1. Juan Carlos Zúñiga-Pflücker, University of Toronto, Sunnybrook Research Institute, Canada

Ethics

Animal experimentation: All mice were bred and maintained under pathogen-free conditions in an American Association of Laboratory Animal Care-approved facility at the University of California, Berkeley. The University of California, Berkeley Animal Use and Care Committee approved all procedures (Animal Care and Use Protocol #AUP-2016-07-9006).

Version history

  1. Received: December 3, 2020
  2. Accepted: April 21, 2021
  3. Accepted Manuscript published: April 22, 2021 (version 1)
  4. Version of Record published: May 12, 2021 (version 2)

Copyright

© 2021, Lutes 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. Lydia K Lutes
  2. Zoë Steier
  3. Laura L McIntyre
  4. Shraddha Pandey
  5. James Kaminski
  6. Ashley R Hoover
  7. Silvia Ariotti
  8. Aaron Streets
  9. Nir Yosef
  10. Ellen A Robey
(2021)
T cell self-reactivity during thymic development dictates the timing of positive selection
eLife 10:e65435.
https://doi.org/10.7554/eLife.65435

Share this article

https://doi.org/10.7554/eLife.65435

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