Nature 373, 620 - 623 (16 February 1995); doi:10.1038/373620a0

Selective requirement for MAP kinase activation in thymocyte differentiation

Jose Alberola-lla^*†, Katherine A. Forbush^*†, Rony Seger^‡§, Edwin G. Krebs^‡§ & Roger M. Perlmutter^*†§¶

Departments of ^* Immunology, ^‡ Pharmacology, ^§Biochemistry,^¶ Medicine (Medical Genetics) and ^† Howard Hughes Medical Institute, University of Washington SL-15, Seattle, Washington 98195, USA
Present address: Department of Membrane Research and Biophysics, The Weizmann Institute of Science, Rehovot 76100, Israel.

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^1–5. 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^6–9, 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 photo-receptor cell specification in Drosophila ¹⁰ and vulval cell differentiation in Caenorhabditis elegans ¹¹ suggesting that general rules for cell-type specification could apply among all metazoans.

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