The signals and growth factors required for the development of T cells are largely unknown. During early fetal thymus ontogeny, a variety of cell surface molecules are expressed which could potentially serve as transducers of activation signals. We found that both interleukin-2 (IL-2) and BSF-1/IL-4 are produced upon activation of fetal thymocytes through Thy-1 and CD3-activation. We have therefore produced transgenic mice with a disability in IL-2 production and are currently exploring early T-cell development in such mice. These, as well as other lymphokines currently investigated, could play a role not only as growth factors, but, as preliminary studies indicated, also as differentiation factors. The potential role of the IL-2 and IL-2 receptors (IL-2R) pathway is not limited to the fetal thymus: the regenerating thymus after radiation and after bone marrow transplantation goes through a stage in which the majority of the CD4- CD8-cells express IL-2R; and blocking of the IL-2R results in arrested T-cell development also in this model. Finally, a panel of early fetal thymic cell lines has been derived by v-myc/v-raf transformation, and is currently being analyzed with respect to the status of expression of all T-cell differentiation antigens, and susceptibility of several differentiation inducing regimens.