Egr2 Is Required for Bcl-2 Induction during Positive Selection

Abstract

The repertoire of TCR specificities is established by a selection process in the thymus, during which precursor survival and maturation is dictated by the nature of the TCR signals. The differences in signals that determine whether precursors will survive and mature or be induced to die remain poorly understood. Among the molecular effectors involved in executing the differentiation process initiated by TCR-ligand interactions is a family of Zn-finger transcription factors termed early growth response genes (Egr). Indeed, ablation of the Egr1 gene impairs ligand-induced maturation (positive selection) but not ligand-induced deletion (negative selection). The partial impairment of positive selection by Egr1 deficiency is not enhanced by simultaneous deletion of another Egr family member, Egr3. Accordingly, we asked whether this results from compensation by another family member, Egr2. In this manuscript, we demonstrate that deletion of Egr2 impairs positive selection of both CD4 and CD8 single-positive thymocytes. Interestingly, many of the genes involved in positive selection and T cell differentiation are up-regulated normally in the Egr2-deficient thymocytes. However, Bcl-2 up-regulation is not sustained during late stages of positive selection. This defect is at least partially responsible for the developmental blockade in Egr2-deficient thymocytes, as enforced expression of Bcl-2 rescues T cell development in Egr2−/− thymocytes. Taken together, these data suggest that Egr2 plays a central role in the up-regulation of the survival molecule Bcl-2 during positive selection.

Early growth response 2 regulates the survival of thymocytes during positive selection

“…We also bred Egr2 f/f CD4Cre mice with Tg mice expressing either the OTII TCR, in which thymocytes are selected into the CD4 lineage, or the F5 TCR, in which thymocytes are selected into the CD8 lineage, both on RAG-deficient backgrounds to preclude rearrangement and expression of endogenous TCR. In line with other workers [26], we found that on an …”

“…Recently, analysis of mice in which Egr2 was deleted in DN thymocytes has shown that it is not required for negative selection, but that positive selection of both CD4 and CD8 lineages is impaired in the absence of Egr2. This defect is at least partially due to increased apoptosis as it is rescued by overexpression of the survival factor Bcl-2 [26]; however, the mechanism by which Egr2 might be regulating survival has not been established.…”

Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1)-mediated Bcl-2 Induction Prolongs Macrophage Survival

“…The expression of Egr2 is dependent on ERK and calcineurin signaling; the endogenous repressor Nab2 inhibits Egr2 in neurons and T cells (30, 36, 60 -62). Induction of anti-apoptotic protein Bcl-2 is regulated by Egr2 during positive selection and survival of thymocytes (27,29). Egr2 polymorphisms have been associated with altered immune response in SLE and neuropathies related to survival of inflammatory cells (63)(64)(65).…”

“…Induction of Bcl-2 has been shown to be regulated by Egr2 during positive selection and survival of thymocytes (27,29). Egr proteins comprise a family of transcriptional regulators (Egr1-4) that modulate gene expression involved in the growth, differentiation, and survival of a variety FIGURE 2.…”

“…The mechanisms of up-regulation of Bcl-2 depend on the cell type. In T cell and thymocytes Egr2 plays a central role through the up-regulation of Bcl-2 during positive selection of thymocytes and T cells prolonging cell survival (27). The Egr family of zinc finger transcription factors are early response genes that have been shown to regulate cell proliferation, differentiation, and apoptosis by inducing Bcl-2.…”