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T Cell Activation Results in Conformational Changes in the Src Family Kinase Lck to Induce Its Activation

T cell activation involves the conformational activation of the tyrosine kinase Lck. Conformational Kinase Activation Lck is a tyrosine kinase that is critical for T cell activation, and its activity is induced by the T cell receptor (TCR). Phosphorylation of Lck at various residues either promotes or inhibits its activity, and Lck exists in various phosphorylated states in a T cell. With fluorescence lifetime imaging microscopic analysis of live human T cells and biochemical analyses, Stirnweiss et al. found that TCR activation produced a conformational change in Lck. In vitro studies showed that this “open” conformation of Lck exhibited enhanced kinase activity. Thus, phosphorylation, location, and conformation all potentially contribute to the regulation of Lck activity. The lymphocyte-specific Src family protein tyrosine kinase p56Lck (Lck) is essential for T cell development and activation and, hence, for adaptive immune responses. The mechanism by which Lck activity is directed toward specific substrates in response to T cell receptor (TCR) activation remains elusive. We used fluorescence lifetime imaging microscopy to assess the activation-dependent spatiotemporal changes in the conformation of Lck in live human T cells. Kinetic analysis of the fluorescence lifetime of Lck biosensors enabled the direct visualization of the dynamic local opening of 20% of the total amount of Lck proteins after activation of T cells with antibody against CD3 or by superantigen-loaded antigen-presenting cells. Parallel biochemical analysis of TCR complexes revealed that the conformational changes in Lck correlated with the induction of Lck enzymatic activity. These data show the dynamic, local activation through conformational change of Lck at sites of TCR engagement.