Small molecule inhibition of Csk alters affinity recognition by T cells

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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 (Csk^AS) whose catalytic activity is specifically and rapidly inhibited by a small molecule. Inhibition of Csk^AS during TCR stimulation led to stronger and more prolonged TCR signaling and to increased proliferation. Inhibition of Csk^AS 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.

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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.
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.
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.
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.
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.
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.
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.

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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.