Small molecule inhibition of Csk alters affinity recognition by T cells

  1. Boryana N Manz
  2. Ying Xim Tan
  3. Adam Courtney
  4. Florentine Rutaganira
  5. Ed Palmer
  6. Kevan M Shokat
  7. Arthur Weiss  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Institute of Molecular and Cell Biology, Singapore
  3. University of basel, Switzerland

Abstract

The C-terminal Src kinase (Csk), the primary negative regulator of Src-family kinases (SFK), plays a crucial role in controlling basal and inducible receptor signaling. To investigate how Csk activity regulates T cell antigen receptor (TCR) signaling, we utilized a mouse expressing mutated Csk (CskAS) whose catalytic activity is specifically and rapidly inhibited by a small molecule. Inhibition of CskAS during TCR stimulation led to stronger and more prolonged TCR signaling and to increased proliferation. Inhibition of CskAS enhanced activation by weak but strictly cognate agonists. Titration of Csk inhibition revealed that a very small increase in SFK activity was sufficient to potentiate T cell responses to weak agonists. Csk plays an important role, not only in basal signaling, but also in setting the TCR signaling threshold and affinity recognition.

Article and author information

Author details

  1. Boryana N Manz

    Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ying Xim Tan

    Division of Cancer Genetics and Therapeutics, Laboratory of Chromatin, Epigenetics and Differentiation, Institute of Molecular and Cell Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Adam Courtney

    Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Florentine Rutaganira

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ed Palmer

    Departments of Biomedicine and Nephrology, University Hospital Basel, University of basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Kevan M Shokat

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Arthur Weiss

    Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States
    For correspondence
    art.weiss@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.

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 (#AN086836, AN107127) of the University of California, San Francisco.

Reviewing Editor

  1. Shimon Sakaguchi, Osaka University, Japan

Publication history

  1. Received: April 14, 2015
  2. Accepted: August 22, 2015
  3. Accepted Manuscript published: August 24, 2015 (version 1)
  4. Version of Record published: September 14, 2015 (version 2)

Copyright

© 2015, Manz 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. Boryana N Manz
  2. Ying Xim Tan
  3. Adam Courtney
  4. Florentine Rutaganira
  5. Ed Palmer
  6. Kevan M Shokat
  7. Arthur Weiss
(2015)
Small molecule inhibition of Csk alters affinity recognition by T cells
eLife 4:e08088.
https://doi.org/10.7554/eLife.08088
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