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 this pathway in CD8 lineage commitment remains controversial. We show here that the differentiation of isolated cultured thymocytes to the CD8 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, CD4 lineage commitment is promoted by a stronger stimulus for longer duration than required for CD8 lineage commitment. Interestingly, CD4 lineage commitment 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 commitment is altered to CD4 commitment if the thymocyte achieves a threshold level of active MAPK within a certain time frame.