Elevated and sustained Egr1 and Egr2 expression controls NKT lineage differentiation in response to TCR signaling

TCR-driven interactions determine the lineage choice of CD4(+)CD8(+) thymocytes, but the molecular mechanisms that induce the lineage-determining transcription factors are unknown. Here we show that TCR-induced Egr2 and Egr1 proteins had elevated and prolonged expression in NKT lineage precursors compared with conventional lineages. ChIP-seq analysis uncovered that Egr2 directly bound and activated the promoter of Zbtb16 which encodes the NKT lineage-specific transcription factor PLZF. Egr2 also bound the Il2rb promoter and controlled the responsiveness to IL-15, which signals the terminal differentiation of the NKT lineage. Thus, we propose that elevated and persistent Egr2 levels specify the early and late stages of NKT lineage differentiation, providing a discriminating mechanism that enables TCR signaling to instruct a thymic lineage.