Abstract
T cell receptor (TCR) signaling is initiated by Src-family kinases (SFKs). To understand how C-terminal Src kinase (Csk), the negative regulator of SFKs, controls the basal state and the initiation of TCR signaling, we generated mice expressing a PP1-analog inhibitor-sensitive Csk variant (CskAS). Inhibition of CskAS in thymocytes, without TCR engagement, induced potent SFK activation and proximal TCR signaling up to phospholipase C-γ1 (PLC-γ1). Surprisingly, increases in inositol phosphates (InsP), intracellular calcium and Erk phosphorylation were impaired. Altering the actin cytoskeleton pharmacologically or providing CD28 costimulation rescued these defects. Thus, Csk plays a critical role in preventing TCR signaling. However, our studies also revealed a requirement for actin remodeling, initiated by costimulation, for full TCR signaling.
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