Small molecule inhibition of Csk alters affinity recognition by T cells
Boryana N Manz,
Ying Xim Tan,
Adam H Courtney,
Florentine Rutaganira,
Ed Palmer,
Kevan M Shokat,
Arthur Weiss
Affiliations
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
Ying Xim Tan
Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States
Adam H 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
Florentine Rutaganira
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
Ed Palmer
Departments of Biomedicine and Nephrology, University Hospital Basel, University of basel, Basel, Switzerland
Kevan M Shokat
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
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; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
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.
