1. Immunology and Inflammation
  2. Physics of Living Systems
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Light-based tuning of ligand half-life supports kinetic proofreading model of T cell signaling

  1. Doug K Tischer
  2. Orion David Weiner  Is a corresponding author
  1. University of California, San Francisco, United States
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Cite this article as: eLife 2019;8:e42498 doi: 10.7554/eLife.42498

Abstract

T cells are thought to discriminate self from foreign peptides by converting small differences in ligand binding half-life into large changes in cell signaling. Such a kinetic proofreading model has been difficult to test directly, as existing methods of altering ligand binding half-life also change other potentially important biophysical parameters, most notably the mechanical stability of the receptor-ligand interaction. Here we develop an optogenetic approach to specifically tune the binding half-life of a chimeric antigen receptor without changing other binding parameters and provide direct evidence of kinetic proofreading in T cell signaling. This half-life discrimination is executed in the proximal signaling pathway, downstream of ZAP70 recruitment and upstream of diacylglycerol accumulation. Our methods represent a general tool for temporal and spatial control of T cell signaling and extend the reach of optogenetics to probe pathways where the individual molecular kinetics, rather than the ensemble average, gates downstream signaling.

Article and author information

Author details

  1. Doug K Tischer

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Orion David Weiner

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    orion.weiner@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1778-6543

Funding

Genentech Foundation (Graduate Student Fellowship)

  • Doug K Tischer
  • Orion David Weiner

National Institutes of Health (GM109899)

  • Orion David Weiner

Novo Nordisk

  • Orion David Weiner

National Science Foundation (DBI-1548297)

  • Orion David Weiner

National Institutes of Health (GM118167)

  • Orion David Weiner

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

Copyright

© 2019, Tischer & Weiner

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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