Small molecule inhibition of Csk alters affinity recognition by T cells

Elife. 2015 Aug 24;4:e08088. doi: 10.7554/eLife.08088.

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.

Keywords: Src kinases; cell biology; immunology; lymphocyte; mouse; receptors; signal transduction; tyrosine phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CSK Tyrosine-Protein Kinase
  • Cell Proliferation
  • Enzyme Inhibitors / metabolism*
  • Mice
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction / drug effects
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology*
  • src-Family Kinases / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Receptors, Antigen, T-Cell
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases