TY - JOUR TI - Small molecule inhibition of Csk alters affinity recognition by T cells AU - Manz, Boryana N AU - Tan, Ying Xim AU - Courtney, Adam H AU - Rutaganira, Florentine AU - Palmer, Ed AU - Shokat, Kevan M AU - Weiss, Arthur A2 - Sakaguchi, Shimon VL - 4 PY - 2015 DA - 2015/08/24 SP - e08088 C1 - eLife 2015;4:e08088 DO - 10.7554/eLife.08088 UR - https://doi.org/10.7554/eLife.08088 AB - 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. KW - signal transduction KW - receptor KW - lymphocyte KW - Src kinase KW - tyrosine phosphorylation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -