Activation of the extracellular signal-related kinase mitogen-activated protein kinase pathway discriminates CD4 versus CD8 lineage commitment in thethymus

We have investigated the role of the mitogen-activated protein kinase (MAPK ) pathway in the differentiation of CD4(+) and CD8(+) T cells by looking sp ecifically at the effects of inhibitors of MAPK-activating enzyme, MAPK/ext racellular signal-related kinase (ERK) kinase (MEK), during the positive se lection step from double-positive to single-positive (SP) thymocytes, Using a variety of transgenic/knockout mouse strain combinations that fail to di fferentiate individual lineages of SP thymocytes together with genetically engineered F(ab')(2) reagents that induce maturation preferentially to eith er the CD4 or CDS subpopulations, we show that induction of CD4 differentia tion cells is highly sensitive to levels of MEK inhibition that have no eff ect on CDS maturation. In addition, the presence of MEK inhibitor is able t o modify signals that normally induce CD4 differentiation to instead promot e CD8 differentiation. Finally, we show that continuous culture in the pres ence of inhibitor interferes with TCR up-regulation in SP thymocytes, sugge sting that MAPK signaling may be involved in final maturation steps for bot h lineages, These data indicate that there is discrimination in the biochem ical pathways that are necessary to specify CD4 and CD8 lineage commitment and can reconcile previously conflicting' reports on the influence of MAPK activation in commitment and maturation of thymocytes.