UC San Diego

The Tec family non-receptor tyrosine kinase, Interleukin-2 Inducible Tyrosine Kinase (Itk), is an enigmatic enzyme that plays a key role in T cell receptor (TCR)-initiated signaling. In a kinase-dependent fashion, Itk directly and significantly affects the regulation of Phospholipase C gamma-1 (PLC[gamma]1) and the consequent mobilization of Ca²⁺. In a kinase-independent manner, Itk indirectly and significantly participates in the regulation of T cell cytoskeletal reorganization necessary to generate a productive T cell response. However, neither of these Itk functions lead to the complete activation of a T cell. Rather, Itk serves as an important mediator of T cell signals, enabling a tempered response to antigen necessary for the development and differentiation of a naïve T cell. The following dissertation includes a review of the scientific literature covering Itk, the characterization of the Itk protein domains necessary for its activation and localization through TCR engagement, the involvement of Itk in the modification of actin-mediated events emanating from the TCR, the discovery of a soluble ligand affecting Itk recruitment, and the development of an inhibitor specific for Itk activity. The collective incorporation of the data presented herein provides evidence that Itk serves as a modulator, or rheostat, critically fine-tuning the T cell response to antigen