Early growth response gene 3 regulates thymocyte proliferation during the transition from CD4-CD8- to CD4+CD8+1

In thymocytes developing in the alphabeta lineage, the transition from CD4, CD8 double negative (DN) to CD4, CD8 double positive (DP) is associated with several rounds of cell division and changes in the expression of multiple genes. This transition is induced by the formation of a pre-TCR that includes a rearranged TCR beta-chain and the pre-TCR alpha-chain. The mechanism by which the pre-TCR influences both gene expression and proliferation has not been defined. We have evaluated the role played by early growth response gene 3 (Egr3) in translating pre-TCR signals into differentiation and proliferation. Egr3 is a transcriptional regulator that contains a zinc-finger DNA binding domain. We find that Egr3-deficient mice have a reduced number of thymocytes compared with wild-type mice, and that this is due to poor proliferation during the DN to DP transition. Treatment of both Egr3(+/+) and Egr3(-/-) mice on the Rag1(-/-) background with anti-CD3epsilon Ab in vivo results in similar differentiation events, but reduced cell recovery in the Egr3(-/-) mice. We have also generated transgenic mice that express high levels of Egr3 constitutively, and when these mice are bred onto a Rag1(-/-) background they exhibit increased proliferation in the absence of stimulation and have pre-TCR alpha-chain and CD25 down-regulation, as well as increased Calpha expression. The results show that Egr3 is an important regulator of proliferation in response to pre-TCR signals, and that it also may regulate some specific aspects of differentiation.