Selective requirement for MAP kinase activation in thymocyte differentiation.

ENGAGEMENT of the T-cell receptor (TCR) with cognate ligands provokes different outcomes depending on the developmental stage of the T cell and on the properties of the ligand. In immature thymocytes TCR stimulation may result in maturation (positive selection) or death (negative selection), whereas in mature T cells it may induce proliferation, death or unresponsiveness. To investigate the different signals involved in these processes, we have analysed the role of the MAP kinase (MAPK) cascade, which is required for growth-factor-stimulated replication and for differentiation in other cell types, by expressing a catalytically inactive form of MAPK kinase (MEK-1) in thymocytes, thereby blocking MAPK activation. We find that positive selection of these cells is inhibited but that negative selection and TCR-induced proliferation are unaffected. Our results indicate that the intracellular signals regulating lineage commitment in T cells parallel those in photoreceptor cell specification in Drosophila and vulval cell differentiation in Caenorhabditis elegans, suggesting that general rules for cell-type specification could apply among all metazoans.