A dominant-negative transgene defines a role for p56^lck in thymopoiesis

The lymphocyte-specific protein tyrosine kinase p56^lck participates in T cell signaling through functional interactions with components of the T cell antigen receptor complex and the interleukin-2 receptor. Additional insight into the function of p56^lck has now been obtained through the generation of transgenic animals expressing high levels of a catalytically inactive form of this kinase (p56^lckR273). Mice bearing the lckR273 transgene manifested a severe defect in the production of virtually all T lymphocytes. Those exceptional CD3⁺ cells that escaped the effects of the lckR273 transgene were confined primarily to the T cell subset that expresses γ/δ T cell receptors. Remarkably, construction of a dose - response curve for the effects of the lckR273 transgene revealed that developmental arrest of thymocytes occurred at a discrete stage in the normal T cell maturation pathway, corresponding to a point at which thymoblasts ordinarily begin a series of mitotic divisions that result in expansion and maturation. These results suggest that p56^lck normally regulates T cell production by metering the replicative potential of immature thymoblasts.