Interplay between RORγt, Egr3, and E proteins controls proliferation in response to pre-TCR signals

The response of thymocytes to pre-T cell receptor (pre-TCR) signaling includes proliferation and gene rearrangement, two cellular processes that are incompatible. The control of proliferation by pre-TCR signals depends on the activities of the transcription factors ROR gamma t, Egr3, E12, and E47. Here, we describe a regulatory network in which interplay between these factors ensures transient proliferation that is temporally distinct from gene rearrangement. ROR gamma t expression was elevated after pre-TCR signaling, and RORyt promoted gene rearrangement in CD4(+), CD8(+) cells by inhibiting cell division, promoting survival via Bcl-X-L, and inducing Rag2. Egr3 was transiently induced by pre-TCR signals and promoted a distinct proliferative phase by reducing E protein-dependent RORyt expression and interacting with RORyt to prevent induction of target genes. After Egr3 subsided, the expression and function of RORyt increased. Thus, transient induction of Egr3 delays the effects of RORyt and enables pre-TCR signaling to induce both proliferation and gene rearrangement.