Sustained early growth response gene 3 expression inhibits the survival of CD4/CD8 double-positive thymocytes.

In the absence of selection, CD4+, CD8+ double-positive (DP) thymocytes will die after 3-4 days. The mechanism for regulating the life span of DP cells is unknown. Previously, we demonstrated that the zinc finger transcription factor, early growth response gene 3 (Egr3), promotes proliferation during the transition from double negative (DN) to DP. In this study we demonstrate a novel role for Egr3 in controlling DP thymocyte survival in mice. Constitutive transgenic expression of Egr3 in thymocytes increases apoptosis among DP cells and shortens their survival in vitro. In addition, DP cells in Egr3 transgenic mice have poor expression of TCRalpha, and based on the predominant usage of 3' Valpha and 5' Jalpha gene segments, the low level of TCRalpha expression is a result of DP death soon after the initiation of TCRalpha rearrangements. Constitutive transgenic expression of Egr3 results in poor expression of Bcl-x(L) and the thymic isoform of retinoic acid receptor-related orphan receptor gamma (RORgammat) in DP thymocytes, two molecules that are required in DP cells for normal life span. Egr3 expression induced by pre-TCR signals in nontransgenic mice is transient and returns to background levels before RORgammat or Bcl-x(L) is induced. The data support a model in which Egr3 must be transiently induced in response to pre-TCR signals, so that the expression of the prosurvival molecules, RORgammat and Bcl-x(L), can be elevated only after the proliferative signal provided by Egr3 has subsided.