Intracellular signalling plays a crucial role in lymphocyte development and function. A panel of molecules involved in signalling has been described and chemical interactions between these molecules documented. However, it remains largely elusive as to whether and how the activation of an individual signalling molecule contributes to various in vivo physiological phenomena such as control of antigen receptor gene rearrangement, repertoire selection, tolerance induction, peripheral lymphocyte activation and maintenance of immune memory. Since these questions can only be properly addressed in an in vivo system, this project focuses on developing animal models by gene targeting and transgenic approaches, and using cellular, molecular and biochemical methods to analyse the impact of various altered signalling molecules on the development, function and pathology of lymphocytes in vivo. Using classic transgenic and embryonic stem cell technologies, mouse strains transgenic for the CSK tyrosine kinase or a dominant negative form of the Syk tyrosine kinase have been established. To minimize the impact of the transgene expression on the development of animals in early ontogeny, an inducible system was employed to drive the transgene expression. These model systems may allow us to study in detail intracellular signalling mechanisms involved in lymphocyte development and function in a more physiological environment.