Requirement for sustained MAPK signaling in both CD4 and CD8 lineage commitment: A threshold model

Although there is general agreement that the RAS/MAPK signaling pathway is required for positive selection of CD4 T cells in the thymus, the role of t his pathway in CD8 lineage commitment remains controversial. We show here t hat the differentiation of isolated cultured thymocytes to the CDS as well as CD4 T cell lineage is sensitive to MEK inhibition and that both CD4 and CD8 thymocyte differentiation requires sustained MEK signaling. However, CD 4 lineage commitment is promoted by a stronger stimulus for longer duration than required for CD8 lineage commitment. Interestingly, CD4 lineage commi tment is not irreversibly set even after 10 h of signaling, well past early changes in gene expression. These findings are presented in the context of a model of lineage commitment in which a default pathway of CD8 lineage co mmitment is altered to CD4 commitment if the thymocyte achieves a threshold level of active MAPK within a certain time frame. (C) 2001 Academic Press.