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Egr2 Is Required for Bcl-2 Induction during Positive Selection¹

Jens-Peter Holst Lauritsen^*, Sridevi Kurella, Sang-Yun Lee^*, Juliette M. Lefebvre^*, Michele Rhodes^*, José Alberola-Ila^2,3, and David L. Wiest^2,3,*

^* Division of Basic Sciences, Immunobiology Working Group, Fox Chase Cancer Center, Philadelphia, PA 19111; and Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants CA73656, CA87407, CA100144, National Institutes of Health Core Grant P01CA06927, Center Grant P30-DK-50306, and an appropriation from the Commonwealth of Pennsylvania (to D.L.W.) and National Institutes of Health Grant AI059302 (to J.A.I.).

² J.A.I. and D.L.W. should be considered co-senior authors.

³ Address correspondence and reprint requests to Dr. José Alberola-Ila, Oklahoma Medical Research Foundation, Immunobiology and Cancer Research Program, 825 NE 13th Street, Oklahoma City, OK 73104 or David L. Wiest, Fox Chase Cancer Center, Division of Basic Sciences, Immunobiology Working Group, R390, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail addresses: DL_Wiest{at}fccc.edu and Jose-alberola-ila{at}omrf.org

⁴ Abbreviations used in this paper: Tg, transgenic; DP, double positive; SP, single positive; KO, knockout; FTOC, fetal thymic organ culture; HSC, hematopoietic stem cell; int, intermediate.