Figure 6.

Environmental cues during T cell development may shape the epigenetic landscape of CD4 and CD8 T cells. (A) Extracellular signaling from the epithelial stroma is a key to guide the multiple stages of αβ T cell development in the thymus. Notch signaling during the early double-negative (DN) stages of T cell development inhibits potential for other lineages, such as B cell and myeloid cells. After thymocytes successfully pass β-selection, Notch signaling is turned off as a consequence of pre-T cell receptor signaling, and subsequent stages of T cell development exhibit very low levels of Notch signaling. Meanwhile IL-7 signaling at this particular stage is critical for the survival and the proliferation of β-selected cells. IL-7 signaling is terminated in immature CD4⁺CD8⁺ double-positive (DP) thymocytes through downregulation of receptor, which is re-expressed in postpositive selection CD4⁺CD8^lo intermediate cells, which not only provides prosurvival signals but also cues for distinct T cell lineage differentiation. (B) Persistent T cell antigen receptor (TCR) signaling, which has been proposed to desensitize IL-7 signaling and to favor CD4 lineage differentiation, could be a critical environmental cue to instigate the expression and activity of ten eleven translocation (TET) enzymes at the Cd4 locus (right). In contrast, cessation of TCR signaling would allow IL-7R signaling in intermediate cells. This may contribute to CD8 lineage specification and may be a key signal to maintain the activity of DNA methyltransferases at the Cd4 locus and ensure methylation of the locus (left).