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. Two such molecules (i.e., Thy-1 and the epsilon-component of the T3 complex) were explored and shown to function in early fetal thymocyte activation, as evidenced by both induction of proliferation and elaboration of lymphokines. We found that both interleukin-2 (IL-2) and BSF-l/IL-4 are produced upon activation of fetal thymocytes through Thy-I and T3-activation, and are currently exploring, in an in vitro organ culture system, the effect of blocking IL-2 or IL-4 usage on T-cell development, as well as designing transgenic mice with a disability in IL-2 production. 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: blocking of the IL-2R results in arrested T-cell development also in this model. Also, the functionality of IL-2R was determined by Scatchard-plot analysis; the affinities of IL-2R on developing thymocytes (a high-affinity and low-affinity) were remarkably similar to those on IL 2-dependent cell lines. 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.
