1. Immunology and Inflammation
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Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor

  1. O Sascha Yousefi
  2. Matthias Günther
  3. Maximilian Hörner
  4. Julia Chalupsky
  5. Maximilian Wess
  6. Simon M Brandl
  7. Robert W Smith
  8. Christian Fleck
  9. Tim Kunkel
  10. Matias D Zurbriggen
  11. Thomas Höfer
  12. Wilfried Weber
  13. Wolfgang WA Schamel  Is a corresponding author
  1. University of Freiburg, Germany
  2. German Cancer Research Center (DKFZ), Germany
  3. Wageningen UR, Netherlands
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Cite this article as: eLife 2019;8:e42475 doi: 10.7554/eLife.42475

Abstract

The immune system distinguishes between self and foreign antigens. The kinetic proofreading (KPR) model proposes that T cells discriminate self from foreign ligands by the different ligand binding half-lives to the T cell receptor (TCR). It is challenging to test KPR as the available experimental systems fall short of only altering the binding half-lives and keeping other parameters of the interaction unchanged. We engineered an optogenetic system using the plant photoreceptor phytochrome B (PhyB) as a ligand to selectively control the dynamics of ligand binding to the TCR by light. This opto-ligand-TCR system was combined with the unique property of PhyB to continuously cycle between the binding and non-binding states under red light, with the light intensity determining the cycling rate and thus the binding duration. Mathematical modeling of our experimental datasets showed that indeed the ligand-TCR interaction half-life is the decisive factor for activating downstream TCR signaling, substantiating KPR.

Article and author information

Author details

  1. O Sascha Yousefi

    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5304-729X
  2. Matthias Günther

    Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Maximilian Hörner

    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Julia Chalupsky

    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Maximilian Wess

    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Simon M Brandl

    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Robert W Smith

    Laboratory of Systems and Synthetic Biology, Wageningen UR, Wageningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Christian Fleck

    Laboratory of Systems and Synthetic Biology, Wageningen UR, Wageningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Tim Kunkel

    Faculty of Biology, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Matias D Zurbriggen

    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Thomas Höfer

    Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Wilfried Weber

    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Wolfgang WA Schamel

    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
    For correspondence
    wolfgang.schamel@biologie.uni-freiburg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4496-3100

Funding

Deutsche Forschungsgemeinschaft (GSC-4)

  • O Sascha Yousefi
  • Maximilian Hörner

Deutsche Forschungsgemeinschaft (EXC294)

  • Wolfgang WA Schamel

Deutsche Forschungsgemeinschaft (EXC81)

  • Thomas Höfer

Deutsche Forschungsgemeinschaft (EXC2189)

  • Wolfgang WA Schamel

Deutsche Forschungsgemeinschaft (INST 39/899-1 FUGG)

  • Wolfgang WA Schamel

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

Reviewing Editor

  1. Arup K Chakraborty, Massachusetts Institute of Technology, United States

Publication history

  1. Received: October 2, 2018
  2. Accepted: March 5, 2019
  3. Accepted Manuscript published: April 5, 2019 (version 1)
  4. Version of Record published: April 29, 2019 (version 2)

Copyright

© 2019, Yousefi 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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